Structural Analysis and Optimization of NK1 Receptor Antagonists through Modulation of Atropisomer Interconversion Properties

Article abstract of DOI:10.1021/jm030197g

We have previously described a series of antagonists that showed high potency and selectivity for the NK₁ receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here

Full text of DOI:10.1021/jm030197g

J . Med. Chem. 2004, 47, 519-529
519
Str u ctu r a l An a lysis a n d Op tim iza tion of NK1 Recep tor An ta gon ists th r ou gh
Mod u la tion of Atr op isom er In ter con ver sion P r op er ties
J effrey S. Albert,* Cyrus Ohnmacht, Peter R. Bernstein, William L. Rumsey, David Aharony, Yun Alelyunas,
Daniel J . Russell, William Potts, Scott A. Sherwood, Lihong Shen, Robert F. Dedinas, William E. Palmer, and
Keith Russell
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, P.O. Box 15437,
Wilmington, Delaware 19850-5437, and EST, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts 02451
Received April 24, 2003
We have previously described a series of antagonists that showed high potency and selectivity
for the NK1 receptor. However, these compounds also had the undesirable property of existing
as a mixture of interconverting rotational isomers. Here we show that alteration of the
2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK1
receptor affinity for the various conformational forms has facilitated the development of a
detailed NK1 pharmacophore model.
In tr od u ction
The tachykinins are a family of three mammalian
neuropeptides: substance P (SP), neurokinin A (NKA),
and neurokinin B (NKB). The preferred receptors for
these are termed NK1, NK2, and NK3, respectively. The
NK1 receptor is widely distributed in the CNS and
peripheral tissue; SP acts as a neurotransmitter or
neuromodulatory agent. The NK1 receptor may be
involved in several pathophysiological conditions includ-
ing asthma, emesis, anxiety, depression, and pain.1,2
The areas of neurokinin antagonist development have
been extensively reviewed.3-6
We have described the identification of the orally
active, dual NK1/NK2 receptor antagonist ZD6021 (1).7,8
In subsequent work, it was found that, for compounds
related to 1, substitutions at the naphthyl 2-position
altered the NK1/NK2 receptor selectivity. This led to the
identification of ZD4974 (2) as a potent, orally available,
NK1-selective antagonist.9
In compound 2, the naphthalene 2-methoxy substitu-
ent was necessary for NK1 selectivity; however, it also
caused the compound to exist in solution as a mixture
of atropisomers (equilibrating conformational isomers).
Due to the restricted rotations at the amide and carbo-
nyl-aryl bonds (Figure 1), a total of four atropisomers
were evident by high-pressure liquid chromatography
(HPLC) and NMR spectroscopy.
Despite its oral potency, progression of 2 as a poten-
tial drug would be complicated because of the existence
of multiple conformational forms; these could present
significant challenges due to potential safety, analytical,
and manufacturing concerns.10,11 To address this, we
have analyzed the kinetic properties and structure-
activity relationships (SARs) for 2 and for related
naphthyl-substituted analogues. These efforts have led
to the identification of 3, which had biological properties
similar to those of 2, but had improved kinetic proper-
ties and could be isolated in a single conformational
F igu r e 1. Structures of 1-3. Arrows indicate bonds with
restricted rotation.
form. In this paper, we describe the structural and
biological properties of 3, and we propose an NK1
receptor pharmacophore model for its activity.
Ch em istr y
Compounds 3-8 could be accessed from the trisub-
stituted naphthalene 9, which was readily available
from prior work.9 Synthetic procedures are illustrated
for the preparation of 3. Selective demethylation of the
methyl ether in 9 was carried out using magnesium
iodide (Scheme 1).12 The resulting naphthol 10 was
converted to triflate 11, which was coupled with tribu-
tylvinyltin in the presence of lithium chloride, tetraki-
striphenylphosphine palladium, and 2,6-di-tert-butyl-4-
methylphenol to afford 12 in good yield. The vinyl group
was reduced using hydrogen in the presence of pal-
ladium on carbon to afford 13. Using trimethylsilyl
iodide, the methyl ester of 13 was converted to carboxy-
lic acid 14. This material was converted to the acid
chloride and then reacted with N-[(S)-2-(3,4-dichlo-
rophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidi-
nyl]butyl]-N-methylamine7 to give 3. Using analogous
approaches, 4-8 were prepared from 9.
Resu lts
(a ) In flu en ce of th e 2-Na p h th yl Su bstitu en t on
Na p h th yl-Ca r bon yl Bon d Rota tion . For compounds
containing the naphthamide group, rotation is restricted
at the amide and the naphthyl-carbonyl bonds (Figure
1) due to resonance and steric effects. In such systems,
four atropisomers can potentially result since each bond
* To whom correspondence should be addressed at CNS Discovery
Research. Phone: (302) 886-4771. Fax: (302) 886-5382. E-mail:
jeffrey.albert@astrazeneca.com.
10.1021/jm030197g CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/23/2003

520 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Albert et al.
Sch em e 1a
Ta ble 1. Receptor Affinity (pKB) for Substituted Aryl Sulfoxide
Piperidine Analogues of 2a
b
c
compd
R
NK1
NK2
a
Reagents: (i) Mg, I2 (73%); (ii) trifluoromethanesulfonic
1
2
3
4
5
6
7
H
OMe
Et
9.00 ( 0.11
9.50 ( 0.11
9.56 ( 0.04
9.06 ( 0.27
7.80 ( 0.46
7.23 ( 0.18
7.39 ( 0.30
8.30 ( 0.12
7.50 ( 0.03
7.31 ( 0.28
7.10 ( 0.01
6.72 ( 0.33
6.35 ( 0.09
7.27 ( 0.16
anhydride, triethylamine (97%); (iii) tributylvinyltin, lithium
chloride, tetrakis(triphenylphosphine)palladium, and 2,6-di-tert-
butyl-4-methylphenol (91%); (iv) H2 (g), 5% palladium on carbon
(89%); (v) (TMS)I (95%).
Me
CH2CH2CH3
CH2CH(CH3)2
Ph
a
pKB determinations using rabbit pulmonary artery tissue (n
) 2-6). b Agonist ASMSP ((Ac-(Arg6,Sar9,Met(O2)11)SP6-11). c Ago-
nist BANK (â-Ala8NKA(4-10)).
naphthamides.14,16 These studies indicated that the
bond rotation rate was substantially influenced by the
nature of the 2-substituent. This prompted us to exam-
ine a series of analogues of 2 with the goal of either
accelerating bond rotation (to reach the fast exchange
regime) or retarding bond rotation (to enable isolation
and storage of the active component).
(b) 2-Su bstitu ted Na p h th a m id e An a logu es of 2.
A series of 2-substituted naphthamide derivatives were
investigated to identify potent NK1 receptor antagonists
which minimized complications due to multiple atropi-
someric forms. In addition, we sought to find a replace-
ment for the naphthol ether group in 2 to reduce the
potential for metabolic liabilities.
As expected from prior studies,9 the 2-naphthyl-
substituted compounds 3-7 showed reduced receptor
binding affinity for NK2 in comparison to 1 (Table 1).
Additionally, all compounds existed as a mixture of four
conformational forms as evidenced by HPLC and NMR.
Replacement of the methoxy group of 2 with methyl (4)
led to slightly reduced affinity at NK1. Replacement
with ethyl (3) resulted in a retention of high NK1
receptor affinity. Replacement with larger groups (5-
7) led to substantially reduced NK1 receptor affinity.
The most potent among these (3) was selected for
further evaluation in biological and structural studies.
(c) Ra te of Atr op isom er In ter con ver sion for 3.
The four atropisomeric components in the equilibrium
mixture of 3 were separated using preparative HPLC
in a manner similar to that for 2. The individual
components were designated as 3a , 3b, 3c, and 3d in
order of increasing HPLC retention times (these desig-
nations are analogous to those for compounds 2a , 2b,
2c, and 2d in Figure 2). Atropisomer interconversion
was monitored by analytical HPLC starting from each
of the isolated isomers in aqueous solution. Results were
independent of conditions of pH between 4 and 8 and
temperature between 50 and 70 °C. Interconversion
occurred predominately between pair 3a /3d and pair 3b/
3c. Interconversion among all other atropisomers was
minimal under the time scale studied (up to 18 h at 70
°C). The rate for the disappearance and appearance of
F igu r e 2. High-pressure liquid chromatogram of 2 showing
the resolution of the atropisomeric forms (2a -d ). Conditions:
column Phenomonex Luna C18(2) (3 µm, 4.6 × 75 mm), 53%
methanol, 47% water (0.1% TFA), 1.5 mL/min, UV detection
at 220 nM.
can assume two orientations (s-cis and s-trans for the
amide bond, axial-R and axial-S for the naphthyl-
carbonyl bond).13 For 1 and analogues where R ) H
(Figure 1), NMR spectra at room temperature were
broadened due to the presence of multiple conforma-
tional forms. Interconversion between the forms ap-
peared to be relatively rapid since (1) the conformers
could not be resolved by HPLC and (2) moderate heating
(50-60 °C) caused coalescence of the NMR resonances
from the individual conformers.
In such naphthamide systems, it is known that the
rate of interconversion is sensitive to the nature of
substitution at the naphthamide 2- and 8-positions.14,15
Introduction of a methoxy group to the naphthyl ring
(to afford 2) substantially increased the bond rotational
barrier; four distinct components could be observed by
HPLC, shown in Figure 2, and NMR spectroscopy.
Samples that were enriched in the major atropisomer
of 2 (2c in Figure 2) were obtained by preparative HPLC
of the atropisomer mixture. Using analytical HPLC, we
monitored the reequilibration of the atropisomers and
estimated the interconversion half-life to be 2-4 h (pH
7.4, 100 mM phosphate, 37 °C). Because this rate is near
the expected biological lifetime of the compound, it
would be likely that exposure would occur to all atro-
pisomers even if the compound was administered in a
single conformational form. Therefore, it was judged to
be unacceptable for further drug development despite
its potent and selective activity as an NK1 receptor
antagonist.
Systematic studies of bond rotation rates have been
carried out by Clayden for closely related 2-substituted

Atropisomer Modulation in NK1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 521
Ta ble 2. Antagonist Binding to Human Tachykinin Receptors
[Ki (nM)]a
Ta ble 3. In Vitro Receptor Activity (pKB) Using Rabbit
Pulmonary Arterya
b
c
d
compd
NK1
NK2
NK3
NK1
% inhibition at % inhibition at
3
1.24 ( 0.15
1.71 ( 0.43
0.40 ( 0.10
2.94 ( 0.57
6.94 ( 0.85
37 ( 6
23 ( 3
35 ( 4
22 ( 6
33 ( 3
97 ( 11
nde
NK2
[antagonist] ) [antagonist] )
3a
3b
3c
3d
b
e
nde
compd
pKB
100 nMd
10 nMd
pKB
nde
3
9.56 ( 0.04
62
89
51
22
98
ndc
<10
ndc
ndc
73
7.31 ( 0.28
7.11( 0.08
7.79 ( 0.21
6.83 ( 0.11
6.25 ( 0.06
nde
3a
3b
3c
3d
ndc
ndc
ndc
ndc
a
Human tachykinin receptor expressed in mouse erythroleu-
kemia cells, n g 2 determinations. Against [3H]SP. c Against
b
d
[
125I]NKA. Against [125I]MePheNKB. e Not determined.
a
pKB determinations using rabbit pulmonary artery tissue (n
) 2-6). Agonist ASMSP, antagonist concentration 1 nM. c Not
determined. Because these compounds displayed nonpurely com-
b
the corresponding isomer obeyed first-order kinetics and
was pH independent between pH 4 and pH 8. The
activation energy for atropisomer interconversion was
determined to be 24 ( 1 kcal/mol by Arrhenius extrapo-
lation of rate constants obtained at different tempera-
tures. This corresponds to a half-life of about 1.8 days
at 37 °C. The observed interconversion rate is consistent
with rates seen for related systems.14,16 Solid samples
of 3d (as the citrate salt) showed no changes in atropi-
somer distribution upon storage at room temperature
for four weeks; this indicated that any reequilibration
in the solid state must be very slow. Compared to the
expected biological half-life of the compound (discussed
below), the extrapolated half-life at 37 °C is slow (1.8
days); hence, 3 was judged to be acceptable for further
investigation.
(d ) Com p a r ison of Atr op isom er ic F or m s of 3.
Hu m a n Recep tor Bin d in g Affin ity. Receptor binding
affinity was determined for each of the isolated atropi-
somers of 3 (Table 2). By keeping the individual atro-
pisomers chilled during the purification and sample
preparation, we minimized reequilibration. Prior to
initiating studies, we verified that each atropisomer had
a purity level of >95%. An exception was for atropisomer
3a ; some batches had a purity level of only >90%.
We found NK1 receptor binding affinity varied over
approximately a 17-fold range from 0.40 nM (3b) to 6.94
nM (3d ). For each, receptor affinity was higher for NK1
than for NK2. However, selectivity was weak; NK1
receptor affinity was greater than NK2 affinity by only
about 5-20-fold. NK3 receptor affinity was somewhat
weaker (Ki ) 97 nM) for the equilibrium mixture (3);
NK3 receptor affinities for the individual atropisomers
were not determined.
(e) Com p a r ison of Atr op isom er ic F or m s of 3. In
Vit r o Act ivit y. Throughout our tachykinin research
program, for compounds in this series, we have continu-
ally observed that when receptor binding affinity (to
human receptors expressed in mouse erythroleukemia
(MEL) cells) is in the nanomolar range, there tends to
be a poor correlation between these data and measures
of in vivo potency when analyzed in various guinea pig,
rabbit, and gerbil assays. We often observed differences
of 20-50-fold, or even greater, in animal models among
compounds that showed similar, and high, human
receptor binding affinity. This occurs despite the high
homology among human, guinea pig, rabbit, and gerbil
tachykinin receptors. This apparent discrepancy be-
comes more pronounced for compounds of higher affin-
ity; in these cases the human receptor binding affinity
appears to plateau, and greater differences are seen in
the in vivo and tissue models. As a consequence of this,
and the generally good correlation between potency
d
petitive antagonism, activity is evaluated by monitoring the
magnitude of the maximum tissue relaxation response (control
response, (5%); values are expressed as percent inhibition, which
is calculated as 100 - percentage of control response; larger values
indicate greater potency.17 Agonist ASMSP, antagonist concentra-
tion 100 nM. e Agonist BANK, antagonist concentration 1 µM.
measures in multiple animal models, we base our
compound evaluation and SAR analysis on results from
animal models and isolated tissue response data rather
than binding data to human receptors expressed in
mouse erythroleukemia cells.
Pharmacological activity and selectivity were assessed
in vitro using pulmonary artery isolated from rabbit
(RPA). As noted above, rabbit neurokinin receptors are
homologous to human neurokinin receptors. Using RPA,
NK2 receptor potency (pKB) of the individual atropiso-
mers of 3 (Table 3) varied by about 10-fold; 3b was the
most potent (pKB ) 7.79), while 3d was the least (pKB
) 6.25). For the NK1 receptor, 3 induced a suppression
of the maximal response to added agonist. Such behav-
ior is often associated with noncompetitive or partially
competitive antagonism; in these cases, pKB cannot be
determined. However, the pKB value of 3 could be
estimated using very low antagonist concentration to
minimize effects on the maximal relaxation response.
To compare the NK1 receptor antagonist activities
among the individual atropisomers (3a -d at 100 nM),
the magnitude of the inhibition of the maximum ago-
nist-mediated tissue relaxation response in the presence
of antagonist was calculated in comparison to the
agonist-mediated relaxation response in the absence of
drug. Greater antagonist activity was indicated by
increased percent inhibition (Table 3).17 Accordingly,
NK1 receptor activity varied in the following rank
order: 3d > 3a > 3b > 3c (affinity for 3a is likely to be
even weaker than indicated because the tested sample
contained 10% of the most active compound 3d as a
contaminant). At lower antagonist concentration (10
nM) it was clearly demonstrated that antagonist activity
was greater for 3d than for 3a .
It is notable that the ranking of activity for com-
pounds 3a -d is different between human receptor
binding affinity (Table 2) and RPA receptor antagonist
activity (Table 3). As explained above, the apparent
inconsistency between the results in these models has
been previously observed for structurally related com-
pounds; many have shown similar and high receptor
binding affinity in cloned MEL cells although they have
quite different activities in functional models.9 Reasons
for this difference have not been thoroughly investi-
gated, but could be due to factors including differences
in receptor expression or compound exposure in the

522 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Albert et al.
Ta ble 4. Inhibition of ASMSP-Induced Foot-Tapping Response
This is a particular concern for testing in the gerbil foot-
tapping model because the atropisomer ratios could
potentially be influenced by, for example, the presence
of plasma proteins or endogenous rotamases during the
long time course of the experiments (up to 6 h). To
confirm that the potent activity of 3d in the gerbil model
was indeed due to 3d alone (and not due to other
atropisomers which could potentially have accumulated
from interconversion during the experimental time
course), we analyzed the atropisomer distribution in
gerbil plasma samples. Using identical protocols for the
gerbil foot-tapping model, 3d was orally administered
to gerbils (n ) 6). At times of 1 and 6 h following
administration, plasma samples were analyzed by LC-
MS to determine the atropisomer distribution. We found
that the distribution of 3d remained consistent at 95 (
1% from the initial point of dosage, at the 1 h interval,
and at the 6 h interval. The distribution of the major
contaminating atropisomer (3c) also remained constant
at about 4.1%. These results confirm that the suppres-
sion of the foot-tapping response is due to 3d and not
due to other forms.
in Gerbila
% inhibition
of response
% inhibition
of response
compd
compd
3
3a
3b
33 ( 17
1.4 ( 0.8
13 ( 11
3c
3d
0.3 ( 0.1
91 ( 9
a
Determined 6 h after oral dosing of antagonist at 5 umol/kg
and initiated by CNS administration of ASMSP (100 pmol); greater
values indicate higher compound potency. n ) 4-8.
models. Because of this apparent discrepancy, we rely
on a combination of in vivo and tissue-based models to
evaluate compound potency, as explained above.
(f) Com p a r ison of Atr op isom er ic F or m s of 3. In
Vivo CNS Activity a n d P h a r m a cok in etic An a lysis.
Central administration of ASMSP to gerbils induces a
foot-tapping response which can be attenuated by prior
dosing with an orally available CNS-penetrant, NK1
receptor antagonist. This can provide a convenient way
to assess activity of NK1 receptor antagonists.18 Gerbils
were orally treated with antagonist at 5 µmol/kg 6 h
prior to administration of agonist. The CNS activity was
then monitored by comparing the degree of foot-tapping
response with control animals that were treated with
antagonist vehicle only. Among the four atropisomers,
3d showed the greatest NK1 receptor antagonism in the
foot-tapping model (Table 4); this compound also had
the greatest effect in RPA tissue (Table 3).
We note that although 3d showed the highest potency
in the rabbit pulmonary artery tissue functional assay
(Table 3) and the highest potency in the gerbil foot-
tapping assay (Table 4), it did not show the highest
affinity among the four atropisomers to human recep-
tors expressed in MEL cells (Table 2). As explained
above, throughout our tachykinin program, compounds
in this chemical series tend to show better consistency
among rabbit tissue models, guinea pig in vivo models,
and gerbil in vivo models than for binding to human
receptors expressed in MEL cells. For this reason, we
regard the tissue models and in vivo studies (particu-
larly in combination) as a more reliable measure of
compound potency than binding to human receptors
expressed in MEL cells.
Pharmacokinetic analysis indicated that 3 had 37%
oral bioavailability with a biological half-life of about 6
h in dog (Table 5). Since the atropisomer interconversion
rate (approximately 1.8 days) was about 7-fold slower
than the biological elimination rate in dog, it is possible
that dosing with the single atropisomer 3d would result
in minimal exposure to the three other atropisomers.
Unfortunately, we were unable to analyze the atropi-
somer distribution of samples from animal studies (in
biological matrixes) due to insufficient chromatographic
resolution in dog. Pharmacokinetic parameters are
summarized in Table 5.
(g) Str u ctu r a l An a lysis of 3. The atropisomers of
3 could be individually analyzed by NMR because of the
relatively slow interconversion among them. The chemi-
cal shifts from the amide N-methyl protons of 3a and
3b were shifted downfield relative to those of 3c and
3d (Table 6). Such a downfield shift is expected when
the methyl group is oriented near the carbonyl oxygen;
this is possible only in the cis-amide configuration. The
corresponding effect is observed for the H16 protons; in
this case the H16 protons in 3c and 3d are shifted
downfield relative to those of 3a and 3b. Again, this
downfield shift is expected in the trans-amide configu-
ration due to the proximity of those protons to the
amide-carbonyl bond. In this manner, we provisionally
assigned trans-amide configurations to 3c and 3d , and
cis-amide configurations to 3a and 3b.
To determine which was the NK1-preferring atropi-
somer, we compared the potency of each individual
purified component in the rabbit pulmonary tissue
functional model and the gerbil foot-tapping model. At
the time each experiment was initiated, we confirmed
that the atropisomer sample under study was present
at a purity of >95% (with the exception of 3a , which
had a purity level of >90%, containing primarily 3d as
the minor, contaminating species). On the basis of the
potency results from the rabbit pulmonary tissue func-
tional model and the gerbil foot-tapping model, we
assign 3d as the preferred NK1 atropisomer.
It is also notable that the chemical shifts for H8 of
3b and (particularly) 3d are significantly upfield in
comparison to the more typical shifts for H8 in 3a and
3c. The upfield shift of the H8 proton in 3d suggests
that it may be located proximal to the shielding region
of the dichloroaryl ring. NMR data for H4 are included
However, it is possible that the atropisomer distribu-
tion could change during the course of the experiments.
Ta ble 5. Pharmcokinetic Analysis of 3 in Dog (n ) 3)
pharmacokinetic param
result
pharmacokinetic param
result
oral dose (µmol/kg)
formulation
Cmax (ng/mL)
Tmax (h)
10
AUC-PO(0-i) [(ng.h)/mL]
extrapolated AUC (%)
bioavailability (%)
t1/2 (h)
6134 ( 4507
7 ( 2
37.3 ( 6.5
5.9 ( 0.6
75% PEG/saline
662 ( 438
4 ( 1

Atropisomer Modulation in NK1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 523
Ta ble 6. 1H NMR Chemical Shifts of Selected Resonances in
Atropisomers of 3a
H4
H8
H16
NMe
3a
3b
3c
3d
8.53
8.49
8.48
8.44
7.67
6.76
7.63
6.19
3.68
3.62
4.88
4.82
3.30
3.32
2.66
2.64
a
Chemical shifts expressed in parts per million for the midpoint
of the spin system, relative to the peak for tetramethylsilane.
Spectra were acquired at room temperature in CDCl3.
for reference; the chemical shifts are nearly equivalent
for all atropisomers.
F igu r e 3. Structural assignments for atropisomers 3a -d .
NMR had suggested that 3d (and 3c) was oriented
with a trans-amide (vide supra), but the carbonyl-aryl
orientation remained uncertain. We assumed that the
upfield shifting of the H8 proton resulted from some
type of aryl-aryl interaction of the naphthalene with
the dichloroaryl ring. Using molecular mechanics mod-
eling, we compared the low-energy conformers for the
axial-R and axial-S carbonyl structures (each with the
trans-amide). Low-energy conformers with the axial-S
configuration directed H8 toward the dichloroaryl ring
(consistent with NMR data), whereas low-energy con-
formers with the axial-R configuration had H8 directed
away from the dichloroaryl ring. On the basis of this,
we associated 3d with S stereochemistry of the carbo-
nyl-aryl bond. NMR had also suggested that 3b con-
tained a cis-amide; analogous modeling studies com-
paring the axial-R and axial-S carbonyl structures for
the cis-amide-containing 3b allowed us to associate 3b
with S stereochemistry of the carbonyl-aryl bond.
Taken together, we propose the structural assignment
for each of the atropisomers as shown in Figure 3.
Although these data all refer to studies conducted in
CDCl3, similar chemical shift changes were observed for
each atropisomer in deuterated methanol and deuter-
ated dimethyl sulfoxide. Unfortunately, we were unable
to observe nuclear Overhauser effects between H4 or
H8 and the dichloro ring in any of the atropisomers
studied.
These structural assignments are further consistent
with the kinetic results; as noted above, we observed
that the fastest interconversion occurred between pair
3a /3d and pair 3b/3c. Very slow interconversion oc-
curred between all other pairs. According to our struc-
tural assignment, the fastest interconversions would be
due to the simultaneous inversion of both the amide
bond and the carbonyl-aryl bond. Independent rotation
of either the amide or carbonyl-aryl bonds (leading to
direct interconversion between pair 3d /3b, 3b/3a , 3a /
3c, or 3c/3d ) would be much slower according to these
observations.
F igu r e 4. Structure of 8.
tems.16 In these cases, it is understood that inversion
of the carbonyl-aryl bond causes steric clashes with the
amide which are relieved by distortion (and concomitant
rotation) of the amide bond. Amide rotation would
similarly be facilitated by distortion/rotation of the
carbonyl-aryl bond. Such interdependence is referred
to as geared rotation.19
Unfortunately, crystals of 3d were unsuitable for
crystallographic analysis. However, useful crystals were
obtained for the truncated analogue 8 in which the
piperidine group was removed (Figure 4). In solution,
8 also exists as a mixture of atropisomers, but can be
easily crystallized and isolated in a single form. NMR
spectral properties of the crystallized form of 8 are
similar to those of 3d ; the H8 and the NMe signals are
shifted upfield (δ 6.35 and 2.62, respectively). As for 3d ,
these results suggest a conformation involving the trans-
amide and an (S)-carbonyl-aryl bond. Furthermore, 8
does show NK1 receptor antagonist activity.20 For 8, the
trans-amide, (S)-carbonyl amide assignment was con-
firmed by crystallographic analysis (Figure 5). In addi-
tion, the crystal structure shows that the naphthyl and
dichloroaryl rings of 8 are positioned to allow an edge-
to-face aryl-aryl stacking interaction as originally
proposed for 3d on the basis of NMR data. The plane of
the naphthalene is nearly orthogonal to the plane of the
dichloroaryl ring, and the naphthalene H8 is located 3.4
Å from the dichloroaryl ring centroid (2.9 Å from the
nearest carbon of the dichloroaryl ring).
(h ) Develop m en t of a P h a r m a cop h or e Mod el for
3d . Evidence from NMR is consistent with a structural
model for 3d where the dichloroaryl and naphthalene
This type of simultaneous, paired interconversion has
been observed for similar naphthamide-containing sys-

524 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Albert et al.
16 suggest that the aryl rings may adopt either an edge-
to-face or face-to-face interaction. Our results tend to
favor an edge-to-face alignment of the aryl rings. Figure
7 shows the predicted conformations of 3d along with
the reference compounds 15 and 16 when fit using our
optimized pharmacophore model. This overlay suggests
that each compound can adopt an edge-to-face aryl
stacking interaction, and each contains a group which
could serve as a hydrogen bond acceptor (ketal oxygen
for 15 and amide carbonyl for 16).
F igu r e 5. Crystal structure of 8 (relaxed-eye stereo repre-
In summary, our prior studies had identified 2 as a
potent, orally available NK1 receptor antagonist but
which had the undesirable structural property of exist-
ing as a mixture of interconverting atropisomers.9 By
altering the substitution at the 2-position of the naph-
thalene, it was possible to slow the rate of exchange
while improving the NK1 receptor affinity. For the
resulting compound (3), the individual atropisomers
were separated and individually analyzed. Structural
analysis of the most potent atropisomer (3d ) is consis-
tent with an NK1 receptor binding model that involves
an edge-to-face stacking interaction between the dichlo-
roaryl and naphthalene rings, with the naphthalene
amide carbonyl serving as a hydrogen bond acceptor.
This model is consistent with models for other chemi-
cally diverse, high-affinity NK1 receptor antagonists.
sentation with hydrogens omitted for clarity).
F igu r e 6. Potent, selective NK1 receptor antagonists 1534 and
16.29
assume orientations analogous to those seen in the
crystal structure of 8. These results suggest a binding
model involving an edge-to-face stacking interaction
between the dichloroaryl and the naphthalene rings.
An NK1 receptor pharmacophore model involving
stacked aryl rings has been implicated in numerous
structural studies on the basis of crystallographic and
solution experiments21-30 as well as modeling.31-33
Additionally, many NK1 pharmacophore models have
suggested the requirement for a hydrogen bond acceptor
in the vicinity of the aryl stacking region. Consistent
with this, we found that NK1 receptor activity was lost
for the analogue containing the reverse amide, or
replacement of the amide with a sulfonamide (data not
shown). Another example where a hydrogen-bonding
group seems necessary can be found in the development
of MK-86921,34 (15; Figure 6). This is a potent and
selective NK1 receptor antagonist which showed anti-
depressant activity in clinical evaluation.35 The design
of this compound included a ketal oxygen to serve as a
key hydrogen bond acceptor. By building upon this
model, a subsequent family of compounds was developed
which contained a highly preorganized spirocyclic core
and which maintained a ketal oxygen as a critical
hydrogen-bonding acceptor.36
Computational evaluation of the pharmacophore model
was carried out by analysis of a set of compounds related
to 3 (which spanned a wide range of receptor binding
affinity) along with all the structural information known
to us. The software program CATALYST37 was used to
generate and rank possible pharmacophore models. The
appropriateness of a given model was assessed by (1)
correlations between predicted and measured affinity
of the various antagonists and (2) the involvement of
an aryl-aryl stacking interaction and hydrogen bond
acceptor group.
Exp er im en ta l Section
Biologica l Stu d ies. The cloning, heterologous expression,
and scale-up growth of MEL cells transfected with the NK1,
NK2, or NK3 receptor were conducted as previously described
for the human NK2 receptor.38-41 The human NK1 receptor was
identical to that reported previously,42,43 whereas the human
NK3 receptor differed from the genomic sequence at AA439
(Cys vs Phe).44,45 Ligand binding assays were conducted with
[3H]SP (for NK1), [3H]NKA (for NK2), and [125I]MePheNKB (for
NK3). Cloning of NK1, NK2, and NK3 receptors was conducted
as published.46 Isolated tissue responses (pKB) and pulmonary
mechanics studies were carried out as previously described.8
For pKB determinations, different antagonist concentrations
were used according to the affinity of the compound under
study; concentrations ranged from 10 nM (for the highest
affinity antagonists) to 10 µM (for lower affinity antagonists).
In the gerbil foot tap model, gerbils were orally treated with
antagonist at 5 mmol/kg 6 h prior to administration of ASMSP
agonist (100 pmol). The CNS potency was then monitored by
comparing the degree of foot tapping response with control
animals that were treated with antagonist vehicle only.18
Bioa va ila bility An a lysis. Compounds were administered
to dog (n ) 3) at 1-10 µmol/kg by iv bolus injection or at 10-
100 µmol/kg orally as a solution in 75% polyethylene glycol
400 in normal saline. Blood samples were taken via surgically
implanted cannula or by venipuncture over a 24 h period, and
plasma was analyzed for unchanged compound by high-
pressure liquid chromatography-mass spectroscopy (LC-MS).
Kin etic An a lysis. Solutions of each isolated atropisomer
(at approximately 1.4 uM) were incubated in 10 mM buffer
solution in the presence of 20% 2-methoxyethanol. The buffer
solution was prepared using sodium phosphate or sodium
acetate with ionic strength adjusted to 100 mM using sodium
periodate. The solutions were incubated in an HPLC autosam-
pler holder connected to an external circulator for temperature
control, and the reequilibration process was monitored periodi-
cally by HPLC at 50, 60, and 70 °C.
Molecu la r Mod elin g. For the structural analysis of 3b and
3d , molecular mechanics computations were performed in
vacuo, using the AESOP47 force field and the in-house molec-
ular graphics program ENIGMA.48 Evaluation of the pharma-
cophore model was carried out by analysis of a set of com-
pounds related to 3 (and covering a wide range of receptor
Our proposed model for 3d shares key features with
models for chemically diverse NK1 receptor antagonists
from Merck21 (15) and Takeda29 (16), shown in Figure
6. Structural studies of compounds related to 15 and

Atropisomer Modulation in NK1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 525
F igu r e 7. Structures according to the predicted pharmacophore model, from the top 3d , 15, and 16. At the bottom is an overlay
of the above three in the same orientation (relaxed-eye stereoview with hydrogens omitted for clarity).
binding affinity) along with all the structural information
known to us. Using the software program CATALYST,37
various potential pharmacophore models were generated that
were consistent with the binding affinity results (correspond-
ing to correlations between predicted and measured affinity
of the various antagonists). The pharmacophore models were
inspected visually and selected for further analysis on the basis
of similarity to reported crystal structures and literature
pharmacophore models. No single pharmacophore model iden-
tified by the program contained all the features implicated in
the literature as important for biological activity. However,
two pharmacophore models were generated that did contain
many of the key features implicated; these were then merged
in CATALYST.
temperature, diethyl ether (80 mL), benzene (30 mL), and
iodine (12.62 g, 49.7 mmol) were added. The reaction mixture
was heated under reflux for 2 h, and the iodine color dis-
sipated. After being cooled to room temperature, this solution
was transferred to methyl 3-cyano-2-methoxy-1-naphthoate9
(9) (10 g, 41.4 mmol) in benzene (30 mL) via syringe. The flask
was washed with benzene (15 mL), and a yellow precipitate
formed during the addition. The reaction mixture was heated
under reflux for 1 h. HCl (1 N) and ethyl acetate were added,
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with saturated Na2S2O4,
NaCl, and water, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash chromatography
eluting with dichloromethane (DCM) to afford the product
(6.88 g, 73% yield) as a yellow solid: 1H NMR δ 12.82 (s, 1 H),
8.81-8.78 (d, 1 H), 8.32 (s, 1 H), 7.83-7.82 (d, 1 H), 7.70 (t, 1
H), 7.50 (t, 1 H), 4.16 (s, 3 H); MS (negative ion mode) m/e
225.92 (M - 1).
Meth yl 3-Cyan o-2-tr iflu or om eth an esu lfon yloxy-1-n aph -
th oa te (11). To a solution of 10 (6.24 g, 27.5 mmol) in DCM
(140 mL) was added triethylamine (4.21 mL, 30.2 mmol)
followed by trifluoromethanesulfonic anhydride (5.05 mL, 30.2
mmol) at 0 °C. The reaction mixture was stirred at room
temperature for 30 min. Saturated NaHCO3 was added, and
the aqueous layer was extracted with DCM. The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated. The crude product was purified by chromatography
(eluting with DCM) to give the product (9.6 g, 97% yield) as a
yellow oil: 1H NMR δ 8.44 (s, 1 H), 8.29-8.04 (d, 1 H), 7.01-
7.98 (d, 1 H), 7.84 (m, 2 H), 4.10 (s, 3 H).
Ch em istr y. 1H NMR spectra were obtained at 300 MHz
using a Bruker DPX 300 spectrometer in CDCl3 and were
referenced to TMS unless otherwise noted. Mass spectral data
were obtained on a Micromass QTOF mass spectrometer. Silica
gel chromatography was performed with ICN silica 32-63, 60
Å. Thin-layer chromatography was done on silica gel 60 F-254
(0.25 mm thickness) plates, and visualization was accom-
plished with UV light. Elemental analyses (C, H, N) were
performed on an Exeter Analytical CE-440 elemental analyzer,
and all compounds are within 0.4% of theory. All materials
were obtained commercially and used without further purifica-
tion. For compounds containing derivatives of 2-substituted
1-naphthoic acids, 1H NMR spectra and HPLC chromatograms
are complex because these compounds exist as a mixture of
slow atropisomers. In these cases, 1H NMR integrations are
not given.
Meth yl 3-Cya n o-2-h yd r oxy-1-n a p h th oa te (10). On the
basis of procedures described by Hauser et al.,12 a flame-dried
250 mL three-neck flask was charged with magnesium metal
(2.42 g, 99.5 mmol). After the flask was cooled to room
Meth yl 3-Cya n o-2-vin yl-1-n a p h th oa te (12). A stirred
solution of 11 (10.0 g, 27.8 mmol), tributylvinyltin (8.95 mL,
30.6 mmol), lithium chloride (3.50 g, 83.4 mmol), tetrakis-
(triphenylphosphine)palladium (0.650 g, 0.556 mmol), and a

526 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Albert et al.
few crystals of 2,6-di-tert-butyl-4-methylphenol in dioxane (125
mL) was heated to reflux for 3 h. To the cooled mixture was
added saturated potassium fluoride solution (150 mL), and the
mixture was stirred at room temperature for 0.5 h. This was
diluted with ethyl acetate and filtered through Celite. The
filtrate was washed with water and saturated sodium chloride,
dried over MgSO4, filtered, concentrated, and purified by
chromatography (eluting with hexane and 5% ethyl acetate/
hexane) to give the product (5.98 g, 91%) as a white solid: 1H
NMR δ 8.31 (s, 1 H), 7.90 (d, 1 H), 7.82 (d, 1 H), 7.75-7.59 (m,
2 H), 7.07-6.97 (m, 1 H), 5.87 (d, 1 H), 5.73 (d, 1 H), 4.01 (s,
3 H); MS m/e 238 (M + 1).
Meth yl 3-Cya n o-2-eth yl-1-n a p h th oa te (13). To a solution
of 12 (5.98 g, 25.2 mmol) in ethanol (500 mL) was added 5%
palladium on carbon (1.5 g); the mixture was shaken under
hydrogen (50 psi) overnight. The mixture was filtered through
Celite and then concentrated to give the product (5.39 g, 89%)
as a light yellow solid: 1H NMR δ 8.28 (s, 1 H), 7.88 (d, 1 H),
7.74 (d, 1 H), 7.67-7.50 (m, 2 H), 4.07 (s, 3 H), 2.96 (q, 2 H),
1.37 (t, 3 H); MS m/e 240 (M + 1).
3-Cya n o-2-eth yl-1-n a p h th oic Acid (14). A mixture of 13
(4.87 g, 20.4 mmol) in trimethylsilyl iodide (10 g) was heated
at 70-75 °C for 24 h. To the cooled solution was added 1 N
HCl, and the mixture was extracted two times with ethyl
acetate. The combined organic layers were dried over MgSO4,
filtered, and concentrated. The crude product was purified by
chromatography (eluting with DCM and then 5% methanol/
DCM with 1% acetic acid) to give the product (4.35 g, 95%) as
a yellow solid: 1H NMR (DMSO-d6) δ 14.03 (s, 1 H), 8.69 (s, 1
H), 8.11 (d, 1 H), 7.89-7.77 (m, 2 H), 7.69 (t, 1 H), 2.91 (q, 2
H), 1.29 (t, 3 H); MS m/e 224 (M + 1).
layer was acidified with 1 N HCl and extracted with ethyl
acetate. The extracts were dried and filtered, and the solvent
was removed to afford the product (0.10 g, 77% yield) as a
white solid: 1H NMR (300 MHz, DMSO-d6) δ 14.02 (s, 1 H),
8.67 (s, 1H), 8.08 (d, 1 H), 7.87-7.62 (m, 3 H), 2.59 (s, 3 H);
MS (negative ion mode) m/e 210 (M - 1).
N-[(S)-2-(3,4-Dich lor op h en yl)-4-[4-[(S)-2-m et h ylsu lfi-
n ylph en yl]-1-piper idin yl]bu tyl]-N-m eth yl-3-cyan o-2-m eth -
yl-1-n a p h th a m id e Citr a te (4). To a solution of 18 (0.10 g,
0.47 mmol) in DCM (5 mL) were added oxalyl chloride (0.052
mL, 0.59 mmol) and a catalytic amount of N,N′-dimethylfor-
mamide. After 2 h, the resulting acid chloride solution was
concentrated under reduced pressure and then redissolved in
DCM (1.5 mL). To this solution were added triethylamine
(0.104 mL, 0.746 mmol) and N-[(S)-2-(3,4-dichlorophenyl)-4-
[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methy-
lamine9 (0.200 g, 0.44 mmol), and the resulting mixture was
stirred overnight. The mixture was diluted with DCM, washed
with saturated sodium bicarbonate, then dried with MgSO4,
filtered, concentrated, and purified by chromatography (eluting
with 1% and then 2% methanol in DCM) to give the product
(0.13 g, 42%). After the mass of free base was determined, the
material was dissolved in methanol, and 1 equiv of citric acid
(38 mg, 0.198 mmol) was added. The mixture was concentrated
to afford the product as a light yellow powder: 1H NMR δ
8.23-8.17 (m), 8.01-7.96 (m), 7.84-7.80 (m), 7.62-7.29 (m),
7.10 (d), 6.96 (d), 6.79 (d), 6.50 (d), 4.60-4.52 (m), 4.19-4.11
(m), 3.85-3.79 (m), 3.56-3.50 (m), 3.34-3.15 (m), 3.04-2.88
(m), 2.74-2.53 (m), 2.32-1.60 (m); MS m/e 646 (M + 1). Anal.
Calcd for C36H37Cl2N3O2S‚C6H8O7‚1.3H2O: C, 58.51; H, 5.56;
N, 4.87. Found: C, 58.50; H, 5.46; N, 4.82.
Meth yl 3-Cyan o-2-pr opyl-1-n aph th oate (19). To a stirred
solution of 9 (0.300 g, 1.24 mmol) in tetrahydrofuran (6 mL)
was added propylmagnesium chloride (2.0 M in ethyl ether,
0.46 mL, 0.92 mmol), and the mixture was stirred at room
temperature for 22 h. The reaction was treated with water
and DCM, the layers were separated, and the aqueous layer
was extracted with three more portions of DCM. The combined
organic extracts were dried (Na2SO4) and filtered, and the
solvent was removed under reduced pressure to yield the
product (0.226 g, 72% based on ester): 1H NMR δ 8.28 (s, 1H),
7.88 (d, 1H), 7.76 (d, 1H), 7.67 (m, 1H), 7.58 (t, 1H), 4.07 (s,
3H), 2.91 (m, 2H), 1.77 (m, 2H), 1.05 (t, 3H).
3-Cya n o-2-p r op yl-1-n a p h th oic Acid (20). A mixture of
19 (0.227 g, 0.91 mmol) and pyridine hydrochloride (2.27 g,
19.6 mmol) was heated at 180 °C for 45 min. After being cooled
to room temperature, the solidified mass was treated with
water and DCM, the layers were separated, and the aqueous
layer was extracted with three additional portions of DCM.
The combined organic extracts were dried (Na2SO4) and
filtered, and the solvent was removed under reduced pressure
to yield the product (0.193 g, 89%) as a white solid: 1H NMR
δ 8.33 (s, 1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.73 (t, 1H), 7.62 (t,
1H), 3.06 (m, 2H), 1.85 (m, 2H), 1.10 (t, 3H).
N-[(S)-2-(3,4-Dich lor op h en yl)-4-[4-[(S)-2-m et h ylsu lfi-
n ylph en yl]-1-piper idin yl]bu tyl]-N-m eth yl-3-cyan o-2-eth yl-
1-n a p h th a m id e Citr a te (3). To a solution of 14 (0.14 g, 0.62
mmol) in DCM (5 mL) were added oxalyl chloride (0.07 mL,
0.78 mmol) and a catalytic amount of N,N′-dimethylforma-
mide. After 2 h, the resulting acid chloride solution was
concentrated under reduced pressure and then redissolved in
DCM (3 mL). To this solution were added triethylamine (0.14
mL, 1.0 mmol) and N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-
methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine9 (262
mg, 0.578 mmol), and the resulting mixture was stirred
overnight. The mixture was diluted with DCM, washed with
saturated sodium bicarbonate, then dried with MgSO4, filtered,
concentrated, and purified by chromatography (eluting with
1%, 2%, and 3% methanol/DCM) to give the product (0.286 g,
75%). After the mass of free base was determined, the material
was dissolved in methanol, and 1 equiv of citric acid (81.7 mg,
0.42 mmol) was added. The mixture was concentrated to afford
the product as a white powder: 1H NMR δ 8.31-8.19 (m),
7.99-7.82 (m), 7.57-7.31 (m), 7.14-7.11 (d), 7.00-6.98 (m),
6.80 (d), 6.53-6.50 (m), 4.60 (t), 4.38 (t), 3.69-3.49 (m), 3.32-
2.55 (m), 2.37-1.61 (m), 1.39-1.10 (m); MS m/e 660.32 (M +
1). Anal. Calcd for C37H39Cl2N3O2S‚C6H8O7‚1.70H2O: C, 58.46;
H, 5.75; N, 4.76. Found: C, 58.51; H, 5.63; N, 4.58.
N-[(S)-2-(3,4-Dich lor op h en yl)-4-[4-[(S)-2-m et h ylsu lfi-
n ylp h en yl]-1-p ip er id in yl]bu tyl]-N-m eth yl-3-cya n o-2-p r o-
p yl-1-n a p h th a m id e Citr a te (5). To a solution of 20 (0.193
g, 0.81 mmol) in DCM (3 mL) were added oxalyl chloride (0.088
mL, 1.01 mmol) and N,N′-dimethylformamide (1 drop). After
being stirred at room temperature overnight, the resulting acid
chloride solution was concentrated under reduced pressure and
then redissolved in DCM (3 mL). This solution was added
dropwise to a cooled (0 °C) stirred mixture of triethylamine
(0.112 mL, 0.81 mmol) and N-[(S)-2-(3,4-dichlorophenyl)-4-[4-
[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methy-
lamine9 (366 mg, 0.81 mmol) in DCM (3 mL), and the resulting
mixture was stirred overnight at 0 °C. The reaction mixture
was concentrated and purified by flash chromatography (elut-
ing with 2% methanol/DCM) to afford the product (0.398 g,
73%) as a white solid. The material was dissolved in methanol,
and 1 equiv of citric acid (113 mg, 0.59 mmol) was added. The
mixture was concentrated to afford the product as a white
powder: 1H NMR (DMSO-d6) δ 8.59 (m) 8.08-7.34 (m), 7.10
(m), 6.90 (d), 6.82 (d), 6.35 (d), 4.59 (t), 4.35 (t), 3.66 (dd), 3.51-
Meth yl 3-Cya n o-2-m eth yl-1-n a p h th oa te (17). A stirred
solution of 11 (0.28 g, 0.779 mmol), K3PO4 (0.33 g, 1.55 mmol),
methylboronic acid (0.096 g, 1.55 mmol), and (1,1′-bis(diphe-
nylphosphino)ferrocene)dichloropalladium(II) ethyl dichloride
(64 mg, 0.078 mmol) in tetrahydrofuran (8 mL) was heated at
66 °C for 4.5 h. Saturated aqueous NaHCO3 was added, and
the mixture was extracted three times with ethyl acetate. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by chromatog-
raphy (eluting with 5% and then 8% ethyl acetate/hexane) to
give the product (0.139 g, 79% yield) as a white solid: 1H NMR
δ 8.28 (s, 1 H), 7.88 (d, 1 H), 7.77 (d, 1 H), 7.67 (t, 1 H), 7.55
(t, 1 H), 4.08 (s, 3 H), 2.66 (s, 3 H); MS m/e 226 (M + 1).
3-Cya n o-2-m eth yl-1-n a p h th oic Acid (18). A solution of
17 (0.139 g, 0.617 mmol) in tetrahydrofuran (7.55 mL) and
water (3 mL) was treated with a solution of NaOH (1.3 mL, 1
N). Methanol (0.5 mL) was added, and the mixture was stirred
under reflux for 27 h. The mixture was concentrated, treated
with additional water, and extracted with DCM. The aqueous

Atropisomer Modulation in NK1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 527
3.17 (m) 2.89-2.48 (m), 2.10-1.40 (m), 0.97 (t) 0.76 (t); MS
m/e 674 (M + 1). Anal. Calcd for C38H41Cl2N3O2S‚C6H8O7‚
1.70H2O: C, 58.89; H, 5.89; N, 4.68. Found: C, 58.63; H, 5.54;
N, 4.86.
poured onto saturated NaHCO3 (20 mL); the ethyl acetate
layer was collected, washed with brine, dried (Na2SO4), and
filtered and the solvent removed under reduced pressure. The
resulting brown solid was purified by flash chromatography
(eluting with DCM) to yield the title compound (0.072 g, 90%)
as a white solid: 1H NMR δ 8.41 (s, 1H), 7.96 (t, 2H), 7.70 (m,
2H), 7.46 (m, 5H), 3.64 (s, 3H).
3-Cya n o-2-p h en yl-1-n a p h th oic Acid (24). A solution of
23 (0.072 g, 0.25 mmol), trimethylsilyl iodide (0.46 g, 2.29
mmol), and 3 mL of chloroform was stirred at room temper-
ature overnight, heated under reflux for 5 h, concentrated
to half the original volume, and then stirred at room temper-
ature overnight. The red-brown reaction mixture was diluted
with ethyl acetate and treated with 1 N HCl (5 mL). The
ethyl acetate layer was then washed successively with satu-
rated Na2S2O3 and brine, dried (MgSO4), and filtered and the
solvent removed under reduced pressure to yield the impure
product as a light tan solid (0.098 g): 1H NMR (DMSO-d6) δ
13.68 (br s, 1H), 8.81 (s, 1H), 8.28 (d, 1H), 7.86 (m, 3H), 7.51
(m, 5H).
N-[(S)-2-(3,4-Dich lor op h en yl)-4-[4-[(S)-2-m et h ylsu lfi-
n ylph en yl]-1-piper idin yl]bu tyl]-N-m eth yl-3-cyan o-2-ph en -
yl-1-n a p h th a m id e Citr a te (7). To a solution of 24 (0.068 g,
0.25 mmol) in DCM (2 mL) were added oxalyl chloride (0.036
mL, 0.42 mmol) and N,N′-dimethylformamide (5 µL). After 1.5
h, the resulting acid chloride solution was concentrated under
reduced pressure and then redissolved in DCM (2 mL). To this
solution were added triethylamine (0.097 mL, 0.70 mmol) and
N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-
1-piperidinyl]butyl]-N-methylamine9 (173 mg, 0.38 mmol), and
the resulting mixture was stirred for 2 h. The mixture was
partitioned between DCM and water, the layers were sepa-
rated, the DCM layer was dried (MgSO4) and filtered, and the
solvent was removed under reduced pressure to yield a white
foam. This was purified by flash chromatography (eluting with
2%, 4%, and 5% methanol/DCM containing 0.1% NH4OH) to
afford the product (0.145 g, 82%) as a white foam: 1H NMR δ
8.77-8.73 (m), 8.16-8.05 (m), 7.85-7.25 (m), 7.02 (d), 6.91-
6.86 (m), 6.72 (d), 6.51 (d), 4.19 (t), 3.65-3.58 (m), 3.45-3.22
(m), 3.02-2.28 (m), 2.14-1.42 (m); MS m/e 708.3 (M + 1). The
material was dissolved in methanol, and 1 equiv of citric acid
(39.2 mg, 0.205 mmol) was added. The mixture was concen-
trated to afford the product as a white powder. Anal. Calcd
for C41H39Cl2N3O2S‚1.2C6H8O7‚0.9H2O: C, 60.59; H, 5.32; N,
4.40. Found: C, 60.63; H, 5.13; N, 4.48.
N-[2-(S)-(3,4-Dich lor oph en yl)-4-h ydr oxybu tyl]-N-m eth -
yl-3-cya n o-2-m eth oxy-1-n a p h th a m id e (25). To a solution
of 3-cyano-2-methoxy-1-naphthoic acid (5.04 g, 22.2 mmol) in
DCM (50 mL) under nitrogen were added dropwise oxalyl
chloride (2.32 mL, 26.6 mmol) and a catalytic amount of N,N′-
dimethylformamide. After being stirred for 3 h, the resulting
acid chloride solution was concentrated under reduced pres-
sure, then redissolved in DCM, and added dropwise to a cooled
(0 °C) solution of N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]-
N-methylamine49 (5.51 g, 22.20 mmol) in DCM (200 mL) and
10% aqueous sodium bicarbonate solution (100 mL), and the
resulting mixture was stirred overnight at room temperature.
The organic phase was separated, washed with water (25 mL)
and brine (25 mL), concentrated, and purified by column
chromatography to afford the product (9.3 g, 92%) as a tan
solid: 1H NMR (DMSO-d6) δ 8.67-8.58 (m), 8.07-8.00 (m),
7.72-7.65 (m), 7.64-7.43 (m), 7.42-7.34 (m), 7.02-7.01 (m),
6.98-6.87 (d), 6.77-6.74 (d), 6.31-6.28 (d), 4.55-4.52 (t),
4.35-4.34 (t), 4.03-3.92 (m), 3.78-3.72 (m), 3.68 (s), 3.45-
3.37 (m), 3.29-2.89 (m), 2.73 (s), 2.59-2.49 (m), 1.91-1.78 (m),
1.58-1.46 (m); MS m/e 457 (M + 1).
Meth yl 3-Cya n o-2-isobu tyl-1-n a p h th oa te (21). A stirred
solution of 11 (0.78 g, 2.17 mmol), K3PO4 (0.92 g, 4.33 mmol),
isobutylboronic acid (0.44 g, 4.33 mmol), and (1,1′-bis(diphe-
nylphosphino)ferrocene)dichloropalladium(II) ethyl dichloride
(0.18 g, 0.22 mmol) in tetrahydrofuran (21 mL) was heated at
66 °C for 17 h. Saturated aqueous NaHCO3 was added, and
the mixture was extracted three times with ethyl acetate. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by chromatog-
raphy (eluting with 5% and then 8% ethyl acetate/hexane) to
give a white solid as a mixture (0.36 g) of desired product and
methyl 3-cyano-1-naphthoate. This mixture was separated by
selective basic hydrolysis as follows. A solution of the above
mixture (0.36 g) in tetrahydrofuran (23 mL) and water (9 mL)
was treated with a solution of NaOH (4.3 mL, 1 N). Methanol
(0.5 mL) was added, and the mixture was stirred at room
temperature for 1 h. Under these conditions, only methyl
3-cyano-1-naphthoate was converted to the corresponding
carboxylic acid, and the remaining methyl 3-cyano-2-isobutyl-
1-naphthoate could be easily separated. The mixture was
concentrated, treated with additional water, and extracted
with DCM. The extracts were dried and filtered, and the
solvent was removed to afford the product (0.17 g, 29% yield)
as a colorless oil: 1H NMR δ 8.28 (s, 1 H), 7.88 (d, 1H), 7.73
(d, 1 H), 7.66 (t, 1 H), 7.57 (t, 1 H), 4.06 (s, 3 H), 2.89 (d, 2 H),
2.12 (m, 1 H), 0.97 (d, 6 H).
3-Cya n o-2-isobu tyl-1-n a p h th oic Acid (22). A mixture of
21 (0.17 g, 0.64 mmol) and trimethylsilyl iodide (5 g) was
heated at 70-75 °C for 21 h. HCl (1 N) was added, and the
mixture was extracted three times with ethyl acetate. The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude product was purified by chromatog-
raphy (eluting with DCM and then 5% methanol/DCM with
1% acetic acid) to give the product (0.145 g, 89% yield) as a
yellow solid: 1H NMR (DMSO-d6) δ 14.03 (s, 1 H), 8.69 (s, 1
H), 8.10 (d, 1 H), 7.88-7.72 (m, 2 H), 7.68 (t, 1 H), 2.86 (d, 2
H), 2.08 (m, 1 H), 0.93 (d, 6 H); MS (negative ion mode) m/e
252 (M - 1).
N-[(S)-2-(3,4-Dich lor op h en yl)-4-[4-[(S)-2-m et h ylsu lfi-
n ylph en yl]-1-piper idin yl]bu tyl]-N-m eth yl-3-cyan o-2-isobu -
tyl-1-n a p h th a m id e Citr a te (6). To a solution of 22 (0.145 g,
0.57 mmol) in DCM (3 mL) were added oxalyl chloride (0.06
mL, 0.71 mmol) and a catalytic amount of N,N′-dimethylfor-
mamide. After 2 h, the resulting acid chloride solution was
concentrated under reduced pressure and then redissolved in
DCM (3 mL). To this solution were added triethylamine (0.126
mL, 0.90 mmol) and N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-
methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.24
g, 0.53 mmol),9 and the resulting mixture was stirred over-
night. The mixture was diluted with DCM, washed with
saturated sodium bicarbonate, then dried with MgSO4, filtered,
concentrated, and purified by chromatography (eluting with
1% and then 2% methanol/DCM) to give the product (0.11 g,
28% yield). After the mass of free base was determined, the
material was dissolved in methanol, and 1 equiv of citric acid
(27.9 mg, 0.145 mmol) was added. The mixture was concen-
trated to afford the product as a light yellow powder: 1H NMR
δ 8.30-8.19 (m), 8.01-7.98 (m), 7.82-7.80 (m), 7.61-7.32 (m),
7.10 (d), 6.89 (d), 6.72 (d), 6.43-6.40 (m), 4.71 (t), 4.07 (dd),
3.78 (dd), 3.56-3.25 (m), 3.04-1.78 (m), 1.04-0.84 (m); MS
m/e 688 (M + 1). Anal. Calcd for C39H43Cl2N3O2S‚1.55C6H8O7‚
0.1H2O: C, 58.70; H, 5.67; N, 4.25. Found: C, 58.45; H, 5.48;
N, 4.43.
N-[2-(S)-(3,4-Dich lor oph en yl)-3-car boxypr opyl]-N-m eth -
yl-3-cya n o-2-m et h oxy-1-n a p h t h a m id e (26). Pyridinium
dichromate50 (4.5 g, 12.1 mmol) was added to a solution of 25
(1.5 g, 3.3 mmol) in DMF (20 mL), and the resulting mixture
was stirred for 4 h. After filtration, dilution with ethyl acetate,
and aqueous extraction of the filtrate, the product was purified
by flash chromatography (1.3 g, 84%): 1H NMR (DMSO-d6) δ
12.28 (s), 8.66-8.62 (m), 8.09-7.95 (m), 7.78-7.76 (m), 7.72-
Meth yl 3-Cya n o-2-p h en yl-1-n a p h th oa te (23). A stirred
solution of 11 (0.100 g, 0.28 mmol), K3PO4 (0.118 g, 0.56 mmol),
phenylboronic acid (0.136 g, 1.12 mmol), (1,1′-bis(diphenylphos-
phino)ferrocene)dichloropalladium(II) ethyl chloride (0.023 g,
0.028 mmol), and tetrahydrofuran (8 mL) was heated under
reflux for 1 h and then stirred at room temperature overnight.
The reaction mixture was diluted with ethyl acetate and

528 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3
Albert et al.
(7) Bernstein, P. R.; Aharony, D.; Albert, J . S.; Andisik, D.; Barth-
low, H. G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembo-
fsky, B. T.; Koether, G.; Kosmider, B. J.; Kirkland, K.; Ohnmacht,
C. J .; Potts, W.; Rumsey, W. L.; Shen, L.; Shenvi, A.; Sherwood,
S.; Stollman, D.; Russell, K. Discovery of novel, orally active dual
NK1/NK2 antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2769-
2773.
(8) Rumsey, W. L.; Aharony, D.; Bialecki, R. A.; Abbott, B. M.;
Barthlow, H. G.; Caccese, R.; Ghanekar, S.; Lengel, D.; McCar-
thy, M.; Wenrich, B.; Undem, B.; Ohnmacht, C.; Shenvi, A.;
Albert, J . S.; Brown, F.; Bernstein, P. R.; Russell, K. Pharma-
7.56 (m), 7.52-7.45 (m), 7.40-7.30 (m), 7.11-7.10 (d), 7.04
(s), 7.01 (s), 6.87-6.84 (d), 4.53-4.45 (t), 3.94 (s), 3.92 (s), 3.68
(s), 3.44-3.27 (m), 3.11 (s), 3.02 (s), 2.76-2.73 (m), 2.62 (s),
2.55-2.38 (m); MS m/e 471 (M + 1).
N-[2-(S)-(3,4-Dich lor oph en yl)-3-am in ocar bon ylpr opyl]-
N-m eth yl-3-cya n o-2-m eth oxy-1-n a p h th a m id e (8). To a
stirred solution of 26 (0.50 g, 1.06 mmol) and diisopropylethy-
lamine (0.37 mL, 2.12 mmol) in DCM (20 mL) was added
tetramethylfluoroformamidinium hexaflurophosphate (0.33 g,
1.27 mmol). After 20 min, ammonium hydroxybenzotriazole51
(0.28 g, 2.12 mmol) was added. After 30 min, the solution was
extracted with saturated sodium bicarbonate, 1 M HCl, water,
and brine and then purified by flash chromatography (0.398
g, 80%): 1H NMR (DMSO-d6) δ 8.64-8.62 (m), 8.08-7.94 (m),
7.78-7.72 (m), 7.70 (s), 7.67 (s), 7.63-7.58 (m), 7.56-7.50 (m),
7.46-7.39 (m), 7.36-7.32 (m), 7.11 (bs); 7.01-6.98 (m), 6.85-
6.76 (m), 6.37-6.34 (d), 4.51-4.43 (t), 4.08-3.99 (m), 3.94 (s),
3.91 (s), 3.73-3.71 (m), 3.67 (s), 3.64-3.61 (m), 3.46-3.28 (m),
3.13 (s), 3.11 (s), 3.06 (s), 2.69 (s), 2.62 (s), 2.56-2.44 (m), 2.34-
2.27 (m), 2.16-2.11 (m), 2.07 (s); MS m/e 470 (M + 1). Anal.
Calcd for C24H21Cl2N3O3‚0.5H2O: C, 60.13; H, 4.62; N, 8.76.
Found: C, 60.22; H, 4.77; N, 8.69.
X-r a y Exp er im en ta l Da ta . Com p ou n d 8. This compound
was crystallized from methylene chloride: empirical formula,
C24H21Cl2N3O3‚CH2Cl2; crystal system, monoclinic; space group,
P21; number of molecules per unit cell, 2; lattice parameters,
a ) 10.432(2) Å, b ) 7.0522(4) Å, c ) 18.2035(13) Å, â )
90.825(7)°; unit-cell volume, 1339.1(2) Å3; least-squares struc-
ture refinement on F2 against all data converged at Rw(F2) )
0.1920; conventional R index R(F) ) 0.0689; S (goodness-of-
fit on F2) ) 1.036; x(σ(x)) (Flack absolute structure parameter
and its esd) ) -0.02(4); expected values for x are 0 (within 3
esd’s) for the correct and +1 for the inverted absolute struc-
ture. The crystal structure was solved by direct methods; all
non-hydrogen atoms appeared in the initial Fourier map
except for the methylene chloride molecule, which was identi-
fied after some initial cycles of refinement of the compound
molecule only followed by reassigning the methylene chloride
atoms in the same asymmetric unit. Hydrogen atoms were
generated in the course of refinement with idealized geom-
etries relative to neighboring non-hydrogen atoms. Disorder
was noted at the methyl from the amide N-methyl group and
accounted for in refinement, resulting in two sets of hydrogen
positions offset by 60° with occupation factors nearly equal,
about 0.5. Although the refinement parameters are within
acceptable ranges, the moderate results may be attributed to
the methylene chloride molecule being rather poorly defined,
as seen in Figure 1 by the large thermal ellipsoids, which
suggests that methylene chloride molecules were gradually
escaping from the crystal lattice over the course of continued
exposure to the X-ray beam during data collection.
cological characterization of ZD6021:
a novel, orally active
antagonist of the tachykinin receptors. J . Pharmacol. Exp. Ther.
2001, 298, 307-315.
(9) Albert, J . S.; Aharony, D.; Andisik, D.; Barthlow, H.; Bernstein,
P. R.; Bialecki, R. A.; Dedinas, R.; Dembofsky, B. T.; Hill, D.;
Kirkland, K.; Koether, G. M.; Kosmider, B. J .; Ohnmacht, C.;
Palmer, W.; Potts, W.; Rumsey, W.; Shen, L.; Shenvi, A.;
Sherwood, S.; Warwick, P. J .; Russell, K. Design, synthesis, and
SAR of tachykinin antagonists: Modulation of balance in NK1/
NK2 receptor antagonist activity. J . Med. Chem. 2002, 45, 3972-
3983.
(10) Testa, B.; Carrupt, P.-A.; Gal, J . The so-called “interconversion”
of stereoisomeric drugs: an attempt at clarification. Chirality
1993, 5, 105-111.
(11) Friary, R. J .; Spangler, M.; Osterman, R.; Schulman, L.;
Schwerdt, J . H. Enantiomerization of an atropisomeric drug.
Chirality 1996, 8, 364-371.
(12) Hauser, F. M.; Sengupta, D.; Corlett, S. A. Optically active total
synthesis of Calphostin D. J . Org. Chem. 1994, 59, 1967-1969.
(13) Oki, M. The Chemistry of Rotatonal Isomers; Springer-Verlag:
New York, 1993.
(14) Ahmed, A.; Bragg, R. A.; Clayden, J .; Lai, L. W.; McCarthy, C.;
Pink, J . H.; Westlund, N.; Yasin, S. A. Barriers to rotation about
the chiral axis of tertiary aromatic amides. Tetrahedron 1998,
54, 13277-13294.
(15) Clayden, J .; McCarthy, C.; Helliwell, M. Bonded peri-interactions
govern the rate of racemization of atropisomeric 8-substituted
1-naphthamides. Chem. Commun. 1999, 2059-2060.
(16) Clayden, J .; Pink, J . H. Concerted rotation in a tertiary aromatic
amide: towards a simple molecular gear. Angew. Chem., Int.
Ed. 1998, 37, 1937-1939.
(17) For compounds that displayed nonpurely competitive antago-
nism, activity could be estimated by monitoring the magnitude
of the maximum tissue relaxation response (percent of control
response) to increasing agonist concentration following incuba-
tion of the tissue with the antagonist at a given concentration.
Values are expressed as percent inhibition, which is calculated
by (100 - percentage of control response). Thus, greater an-
tagonist potency would be indicated by greater percent inhibition
and at lower antagonist concentration.
(18) Rupniak, N. M. J .; Tattersall, F. D.; Williams, A. R.; Rycroft,
W.; Carlson, E. J .; Cascieri, M. A.; Sadowski, S.; Ber, E.; Hale,
J . J .; Mills, S. G.; MacCoss, M.; Seward, E.; Huscroft, I.; Owen,
S.; Swain, C. J .; Hill, R. G.; Hargreaves, R. J . In vitro and in
vivo predictors of the anti-emetic activity of tachykinin NK1
receptor antagonists. Eur. J . Pharmacol. 1997, 326, 201-209.
(19) Iwamura, H.; Mislow, K. Stereochemical consequences of dy-
namic gearing. Acc. Chem. Res. 1988, 21, 175-182.
(20) Manuscript in preparation.
(21) Swain, C. J .; Sewart, E. M.; Cascieri, M. A.; Fong, T. M.; Herbert,
R.; MacIntyre, D. E.; Merchant, K. J .; Owen, S. N.; Owens, A.
P.; et al. Identification of a series of 3-(benzyloxy)-1-azabicyclo-
[2.2.2]octane human NK1 antagonists. J . Med. Chem. 1995, 38,
4793-4805.
Ackn owledgm en t. We gratefully acknowledge James
Hulsizer for large-scale synthesis efforts, J ames Hall
for detailed NMR analysis, and Margaret Lin for
crystallography support.
(22) Lowe, J . A., III; Drozda, S. E.; Snider, R. M.; Longo, K. P.; Zorn,
S. H.; Morrone, J .; J ackson, E. R.; McLean, S.; Bryce, D. K.; et
al. The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-meth-
oxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine as a novel,
nonpeptide substance P antagonist. J . Med. Chem. 1992, 35,
2591-2600.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for 8. This material is available free of charge via the
Internet at http://pubs.acs.org.
Refer en ces
(23) Boks, G. J .; Tollenaere, J . P.; Kroon, J . Possible ligand-receptor
interactions for NK1 antagonists as observed in their crystal
structures. Bioorg. Med. Chem. 1997, 5, 535-547.
(24) Caliendo, G.; Grieco, P.; Perissutti, E.; Santagada, V.; Saviano,
G.; Tancredi, T.; Temussi, P. A. Conformational analysis of three
NK1 tripeptide antagonists: A proton nuclear magnetic reso-
nance study. J . Med. Chem. 1997, 40, 594-601.
(25) Veenstra, S. J .; Hauser, K.; Betschart, C. Studies on the active
conformation of NK1 antagonist CGP 49823. Part 1. Synthesis
of conformationally restricted analogs. Bioorg. Med. Chem. Lett.
1997, 7, 347-350.
(26) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, R. M. Discovery of a potent substance P antagonist:
recognition of the key molecular determinant. J . Med. Chem.
1992, 35, 4911-4913.
(1) Stout, S. C.; Owens, M. J .; Nemeroff, C. B. Neurokinin-1 receptor
antagonists as potential antidepressants. Annu. Rev. Pharmacol.
Toxicol. 2001, 41, 877-906.
(2) Chahl, L. A.; Urban, L. A. New developments in tachykinin
research. Pharmacol. Rev. Commun. 1999, 10, 197-203.
(3) Swain, C.; Rupniak, N. M. J . Progress in the development of
neurokinin antagonists. Annu. Rep. Med. Chem. 1999, 34, 51-
60.
(4) Gerspacher, M.; Von Sprecher, A. Dual neurokinin NK1/NK2
receptor antagonists. Drugs Future 1999, 24, 883-892.
(5) Gao, Z.; Peet, N. P. Recent advances in neurokinin receptor
antagonists. Curr. Med. Chem. 1999, 6, 375-388.
(6) Sakurada, T.; Sakurada, C.; Tan-No, K.; Kisara, K. Neurokinin
receptor antagonists: therapeutic potential in the treatment of
pain syndromes. CNS Drugs 1997, 8, 436-447.

Atropisomer Modulation in NK1 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 529
(27) Stevenson, G. I.; Huscroft, I.; MacLeod, A. M.; Swain, C. J .;
Cascieri, M. A.; Chicchi, G. G.; Graham, M. I.; Harrison, T.;
Kelleher, F. J .; Kurtz, M.; Ladduwahetty, T.; Merchant, K. J .;
Metzger, J . M.; MacIntyre, D. E.; Sadowski, S.; Sohal, B.; Owens,
A. P. 4,4-Disubstituted piperidine high-affinity NK1 antago-
nists: Structure-activity relationships and in vivo activity. J .
Med. Chem. 1998, 41, 4623-4635.
(28) Lewis, R. T.; Macleod, A. M.; Merchant, K. J .; Kelleher, F.;
Sanderson, I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball,
R. G.; Hoogsteen, K. Tryptophan-derived NK1 antagonists:
Conformationally constrained heterocyclic bioisosteres of the
ester linkage. J . Med. Chem. 1995, 38, 923-933.
(29) Ikeura, Y.; Ishichi, Y.; Tanaka, T.; Fujishima, A.; Murabayashi,
M.; Kawada, M.; Ishimaru, T.; Kamo, I.; Doi, T.; Natsugari, H.
Axially chiral N-benzyl-N,7-dimethyl-5-phenyl-1,7-naphthyri-
dine-6-carboxamide derivatives as tachykinin NK1 receptor
antagonists: Determination of the absolute stereochemical
requirements. J . Med. Chem. 1998, 41, 4232-4239.
(30) Sisto, A.; Bonelli, F.; Centini, F.; Fincham, C. I.; Potier, E.;
Monteagudo, E.; Lombardi, P.; Arcamone, F.; Goso, C.; et al.
Synthesis and biological evaluation of novel NK-1 tachykinin
receptor antagonists: the use of cycloalkyl amino acids as a
template. Biopolymers 1995, 36, 511-524.
(31) Greenfeder, S.; Cheewatrakoolpong, B.; Anthes, J .; Billah, M.;
Egan, R. W.; Brown, J . E.; Murgolo, N. J . Two related neuroki-
nin-1 receptor antagonists have overlapping but different bind-
ing sites. Bioorg. Med. Chem. 1998, 6, 189-194.
(32) J acoby, E.; Boudon, A.; Kucharczyk, N.; Michel, A.; Fauchere,
J .-L. A structural rationale for the design of water soluble
peptide-derived neurokinin-1 antagonists. J . Recept. Signal
Transduction Res. 1997, 17, 855-873.
(33) Takeuchi, Y.; Shands, E. F. B.; Beusen, D. D.; Marshall, G. R.
Derivation of a 3-dimensional pharmacophore model of sub-
stance P antagonists bound to the neurokinin-1 receptor. J . Med.
Chem. 1998, 41, 3609-3623.
(34) Hale, J . J .; Mills, S. G.; MacCoss, M.; Finke, P. E.; Cascieri, M.
A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J .;
Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupniak, N. M. J .;
Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E.
Structural optimization affording 2-(R)-(1-(R)-3,5-bis(trifluorom-
ethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-
5-yl)methylmorpholine, a potent, orally active, long-acting mor-
pholine acetal human NK-1 receptor antagonist. J . Med. Chem.
1998, 41, 4607-4614.
(37) CATALYST, version 4.5; Molecular Simulations Inc.: San Diego,
CA.
(38) Aharony, D.; Little, J .; Thomas, C.; Powell, S.; Berry, D.;
Graham, A. Isolation and pharmacological characterization of
a hamster urinary bladder neurokinin A receptor cDNA. Mol.
Pharmacol. 1994, 45, 9-19.
(39) Graham, A.; Hopkins, B.; Powell, S. J .; Danks, P.; Briggs, I.
Isolation and characterization of the human lung NK-2 receptor
gene using rapid amplification of cDNA ends. Biochem. Biophys.
Res. Commun. 1991, 177, 8-16.
(40) Huang, R.; Cheung, A.; Mazina, K.; Strader, C.; Fong, T. cDNA
Sequence and heterologous expression of the human neuroki-
nin-3 receptor. Biochem. Biophys. Res. Commun. 1992, 184,
966-972.
(41) Takeda, Y.; Chou, K. B.; Takeda, J .; Sachais, B. S.; Krause, J .
E. Molecular cloning, structural characterization and functional
expression of the human substance P receptor. Biochem. Bio-
phys. Res. Commun. 1991, 179, 1232-1240.
(42) Fong, T. M.; Anderson, S. A.; Yu, H.; Huang, R. R. C.; Strader,
C. D. Differential activation of intracellular effector by two
isoforms of human neurokinin-1 receptor. Mol. Pharmacol. 1992,
41, 24-30.
(43) Gerard, N. P.; Garraway, L. A.; Eddy, R. L., J r.; Shows, T. B.;
Iijima, H.; Paquet, J . L.; Gerard, C. Human substance P receptor
(NK-1): organization of the gene, chromosome localization and
functional expression of cDNA clones. Biochemistry 1991, 30,
10640-10646.
(44) Takahashi, K.; Tanaka, A.; Hara, M.; Nakanishi, S. The primary
structure and gene organization of human substance P and
neuromedin K receptors. Eur. J . Biochem. 1992, 204, 1025-
1033.
(45) Buell, G.; Schulz, M. F.; Arkinstall, S. J .; Maury, K.; Missotten,
M.; Adami, N.; Talabot, F.; Kawashima, E. Molecular charac-
terization, expression and localization of human neurokinin-3
receptor. FEBS Lett. 1992, 299, 90-95.
(46) Aharony, D.; Buckner, C. K.; Ellis, J . L.; Ghanekar, S. V.;
Graham, A.; Kays, J . S.; Little, J .; Meeker, S.; Miller, S. C.; et
al. Pharmacological characterization of a new class of nonpeptide
neurokinin A antagonists that demonstrate species selectivity.
J . Pharmacol. Exp. Ther. 1995, 274, 1216-1221.
(47) AESOP is an in-house molecular mechanics program (Masek,
B.) derived from BIGSTRN-3 (QCPE-514): Nachbar, R., J r.;
Mislow, K. QCPE Bull. 1986, 6, 96.
(48) ENIGMA is an in-house molecular graphics program.
(49) Miller, S. C. (Zeneca Ltd., U.K.). Novel 4-piperidinyl-substituted
lactams as neurokinin 2 receptor antagonists for the treatment
of asthma. PCT Int. Appl. WO 9512577, 1995.
(35) Kramer, M. S.; Cutler, N.; Feighner, J .; Shrivastava, R.; Carman,
J .; Sramek, J . J .; Reines, S. A.; Liu, G.; Snavely, D.; Wyatt-
Knowles, E.; Hale, J . J .; Mills, S. G.; MacCoss, M.; Swain, C. J .;
Harrison, T.; Hill, R. G.; Hefti, F.; Scolnick, E. M.; Cascieri, M.
A.; Chicchi, G. G.; Sadowski, S.; Williams, A. R.; Hewson, L.;
Smith, D.; Carlson, E. J .; Hargreaves, R. J .; Rupniak, N. M. J .
Distinct mechanism for antidepressant activity by blockade of
central substance P receptors. Science (Washington, D.C.) 1998,
281, 1640-1645.
(36) Seward, E. M.; Carlson, E.; Harrison, T.; Haworth, K. E.;
Herbert, R.; Kelleher, F. J .; Kurtz, M. M.; Moseley, J .; Owen, S.
N.; Owens, A. P.; Sadowski, S. J .; Swain, C. J .; Williams, B. J .
Spirocyclic NK1 antagonists I: [4.5] and [5.5]-spiroketals. Bioorg.
Med. Chem. Lett. 2002, 12, 2515-2518.
(50) Corey, E. J .; Schmidt, G. Useful procedures for the oxidation of
alcohols involving pyridinium dichromate in aprotic media.
Tetrahedron Lett. 1979, 399-402.
(51) Bajusz, S.; Ronai, A. Z.; Szekely, J . I.; Graf, L.; Dunai-Kovacs,
Z.; Berzetei, I. A superactive antinociceptive pentapeptide, (D-
Met2, Pro5)-enkephalinamide. FEBS Lett. 1977, 76, 91-92.
J M030197G