The discovery of tropane derivatives as nociceptin receptor ligands for the management of cough and anxiety

Article abstract of DOI:10.1016/j.bmcl.2009.03.031

The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds exhibit high affinity for the nociceptin recept

Full text of DOI:10.1016/j.bmcl.2009.03.031

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2519–2523
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The discovery of tropane derivatives as nociceptin receptor ligands
for the management of cough and anxiety
b
a
a
c
c
Ginny D. Ho a, , John Anthes , Ana Bercovici , John P. Caldwell , Kuo-Chi Cheng , Xiaoming Cui ,
Ahmad Fawzi b, Xiomara Fernandez b, William J. Greenlee a, John Hey b, Walter Korfmacher c, Sherry X. Lu b,
Robbie L. McLeod b, Fay Ng a, April Smith Torhan b, Zheng Tan a, Deen Tulshian a, Geoffrey B. Varty b,
Xiaoying Xu c, Hongtao Zhang b
*
a Department of Chemical Research, CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
c Department of Drug Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery of 1 as a high-affinity ligand for the nociceptin receptor has led to the synthesis of a series
Received 8 January 2009
Revised 9 March 2009
Accepted 10 March 2009
Available online 14 March 2009
of tropane (8-methyl-8-azabicyclo[3.2.1]octane) derivatives as optimized ligands. These compounds
exhibit high affinity for the nociceptin receptor, moderate to excellent selectivity over the opioid
l recep-
tor, and behave as full agonists. In this Letter, we present the synthesis and highlight the structure–activ-
ity relationship of tropane derivatives culminating in the identification of 24 and 32 as potent and orally
active antitussive and anxiolytic agents. The in vitro and in vivo activities, pharmacokinetic profile, and
the hPXR activity, which predicts the potential 3A4 induction in human, are disclosed.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nociceptin receptor
Opioid receptors
Nociceptin/orphanin FQ (N/OFQ)
Anxiolytic-like activity
Antitussive activity
Human pregnane X receptor (hPXR)
Capsaicin-induced cough model in guinea
pigs
Conditioned lick suppression (CLS) model in
rats
Separation-induced guinea pig pups
vocalization assay (GPPV)
The identification of nociceptin/orphanin FQ peptide (N/OFQ) in
1995 represented the first successful use of reverse pharmacology
and led to deorphanization of the nociceptin receptor (NOP).1,2
Subsequently, the N/OFQ–NOP system has been implicated in a
wide range of biological functions, including cough, anxiety, uri-
nary incontinence, sleep disturbance, pain, stress, feeding, learning
and memory, locomotor activity, substance abuse, cardiovascular
function, and Parkinson’s disease.3 Despite the high sequence
gands.4 In this Letter, we report the results of an expanded SAR
study to identify a series of tropane derivatives as nociceptin
receptor agonists. This has led to the discovery of potent and orally
active antitussive and anxiolytic agents.
The lead compound 1 displays high affinity for NOP with bind-
ing affinity of 13 nM and moderate to excellent selectivity over
MOP. KOP, and DOP.
Ph OH
4
homology between the nociceptin receptor and the opioid
l, j,
and d receptors (MOP, KOP, and DOP), and high similarity between
N/OFQ and the opioid peptides, endogenous opioid receptor li-
gands lack affinity for NOP and N/FQ fails to activate the classical
opioid receptors.
NOP Ki = 13 nM
DOP Ki = 1666 nM
N
1
KOP Ki = 364 nM
MOP Ki = 233 nM
2
2'
Previously, we have disclosed a series of N-benzhydryl substi-
tuted 4-hydroxy-4-phenylpiperidines as nociceptin receptor li-
1
Since 4-aryl-4-hydroxypiperidine is known to metabolize to the
potentially neurotoxic 4-arylpyridinium species,5 our SAR develop-
ment has focused on the modification of the piperidine ring. The
* Corresponding author. Tel.: +1 908 740 3502; fax: +1 908 740 7164.
E-mail address: ginny.ho@spcorp.com (G.D. Ho).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.031

2520
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2519–2523
Table 1
employed to prepare isotropane derivatives having the general
SAR of the modified piperidine ring of 1
structure 17 is diagramed in Scheme 2, while the C-3 hydroxy
modified analogs is outlined in Scheme 3.6
Ph
Ph
OH
CH3
OH
CH3
OH
3
Target compounds were tested for affinity at the cloned human
nociceptin receptor expressed in CHO cell membranes by measur-
ing their ability to compete with [125I][Tyr14]nociceptin FQ. The
opioid receptor binding assays were performed on CHO cell mem-
branes expressing the human opioid receptors using [3H]-dipre-
norphine as the radioligand. The Ki values were determined from
dose–response curves. The functional activities of selected com-
pounds were evaluated by their ability to enhance the binding of
OH
Ph
Ph
Ph
N
8
Ph
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
5
2
3
4
a
Compds
MW
cLogP
Kia (nM)
EC50 (nM) (% stim. @ 10
l
M)
NOP MOP
NOP
MOP
[
35S]GTP
cS in the presence of GDP, using membranes isolated from
2
3
4
5
357.5
357.5
369.5
383.5
4.8
4.8
4.6
5.2
142
1571
2.3
738
nd
94
(70%)
nd
161
nd
nd
nd
nd
cells transfected with the nociceptin receptor.7
Selected compounds were evaluated for their antitussive and
anxiolytic-like activity via oral administration. The antitussive
activity was tested in the capsaicin-induced cough model in guinea
pigs.3a The anxiolytic-like effects were assessed in the conditioned
lick suppression (CLS) model in rats and the separation-induced
guinea pig pups vocalization assay (GPPV).8
For the N-8 modifications, a variety of small substituents (Me,
Et, F, Cl, Br, OMe, CN, CH2OH) appear to be tolerated at the C-2 po-
sition of one or both of the phenyl rings on the benzhydryl (data
not shown). Consistent with previous studies on the N-1 modifica-
tions of 1,4 introduction of a methyl or chlorine at C-2 of the benz-
7.5
514
(101%)
a
Values are means of at least 2–3 experiments (nd = not determined).
binding and properties of the modified piperidine analogs 2–5 are
shown in Table 1. Since these compounds generally have better
selectivity over KOP and DOP, only selectivity over MOP will be
presented.
The conformationally constrained analogs 4 and 5 have im-
proved the NOP affinity and selectivity over MOP and produce a
full agonist response. Compound 4 shows a 70-fold decrease in
the functional activity relative to its binding affinity and is not effi-
cacious in the capsaicin-induced cough model in guinea pigs.3a
Since 4 has higher affinity for NOP and lower cLogP, further SAR
development has centered on 4 to improve the functional and
in vivo activities.
OH
N
CHO
Ph
CH2OH
Ph
e
b
f
R1
N
Ph
R1
N
R1
N
The preparations of the N-benzhydryl modified analogs 8 and 9
and the 3-phenyl modified analogs having the general structures
11 and 12 are shown in Scheme 1. Generally diastereomer 11 is
isolated predominantly as the major product. The synthetic routes
31
20
30
d
CO2H
Ph
CN
Ph
c
a
CN
R1
N
10
R1
N
R1
N
18
23
22
g
HN
N
OH
Ph
OH
Ph
O
N
Ph
b
a
NHCO2Me
Ph
CONH2
Ph
k
h
R2
N
R1
N
HN
HCl
R1
N
Me
N
R1
N
7
6
8, 9
24
25
29
8, R2= Bis(2-methylphenyl)methyl
9, R2= Bis(2-chlorophenyl)methyl
i
c
O
HN
NHCH3
NH2
Ph
R
j
OH
O
Ph
d
R1
N
R1
N
OH
R
+
R1
R1
N
R1
N
N
27
26
10
11
12
Scheme 3. Reagents and conditions: (a) TsCH2NC, t-BuOK/EtOH, DME; (b) KHMDS,
PhF/PhCH3; (c) NaOH/(CH2OH)2; (d) DIBAL/toluene; (e) NaBH4/MeOH; (f)
NH2OHꢁHCl, Py., EtOH; (g) concd H2SO4; (h) PhI(OAc)2, KOH/MeOH; (i) TMSI; (j)
MeN@C@O/THF; (k) (1) Me2NCH(OMe)2; (2) NH2NH2ꢁH2O.
R1= Bis(2-chlorophenyl)methyl
Scheme 1. Reagents and conditions: (a) (1) PhLi/THF, ꢀ78 °C; (2) ClC(O)CH(Cl)CH3/
(CH2Cl)2, reflux; (3) MeOH, reflux; (b) R2Br, K2CO3,/CH3CN, 80 °C; (c) (1)
ClC(O)CH(Cl)CH3/(CH2Cl)2, reflux; (2) MeOH, reflux; (3) R1Br, K2CO3/CH3CN, 80 °C;
(d) RLi, RMgBr, RMgCl/THF or Et2O or NaBH4/MeOH.
4
OH
OH
O
OH
O
Ph
Ph
b
a
2
Ar
H3C
N
Cl
N
Bn
N
Bn
N
CH3
Cl
13
15
14
2'
4'
OH
OH
8
9
c
d
Ar
Ar
HN
R1
N
MW = 397.6, cLogP = 5.5
MW=438.4, cLogP=6.0
NOP
MOP
KOP
DOP
K
K
K
K
i = 0.3 nM, EC50 = 12 nM
i = 65 nM, EC50 = 693 nM
i = 131 nM
i = 2854 nM
NOP
MOP
KOP
K
i = 3.4 nM, EC50 = 4 nM
i = 22 nM, EC50 = 337 nM
i = 109 nM
K
16
17
R1 = Bis(2-chlorophenyl)methyl
K
DOP Ki = 3143 nM
Scheme 2. (a) (HCHO)n, BnNH2, AcOH/MeOH, reflux; (b) ArLi/THF or Et2O; (c)
HCO2NH4, Pd(OH)2/C, MeOH, 50 °C; (d) R1Br, K2CO3/CH3CN, 80 °C.
Figure 1. Binding and functional activities of 8 and 9.

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2519–2523
2521
Table 2
To determine whether the hydroxy is tolerated at the equatorial
position, the NOP affinities of the axial and equatorial isomers have
been investigated (Table 3). The hydroxyl group in the axial posi-
tion appears to be essential for the nociceptin receptor binding
since the hydroxyl group in the equatorial position decreases the
NOP affinity considerably (11a–c vs 12a–c).
Antitussive and anxiolytic-like activity of 8 and 9
a,b
Compds
Antitussive activity
ED50a,b(mg/kg)
Anxiolytic-like activity ED50 (mg/kg)
GPPV
Rat CLS
8
9
0.07
0.4
0.5
0.4
1.6
1.4
The NOP affinity of the isotropane analog, an alternative con-
formationally constrained structure has also been examined (Table
4). Compared to the corresponding isotropane analogs 17d and
17e, the tropane derivatives 11d and 11e display improved affinity
for NOP.
The SAR of 3-phenyl modifications of 9 is highlighted in Table 5.
Substituted or unsubstituted aryl, heteroaryl, arylalkyl, hetero-
arylalkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl are toler-
ated at the C-3 equatorial position and produce potent and
selective NOP agonists with moderate to good selectivity over
MOP. Replacement of the phenyl with a heteroatom containing
moiety to reduce the lipophilicity appears to decrease both NOP
and MOP functional activities.
The SAR of the analogs modified at the C-3 hydroxy is shown in
Table 6. It appears that the 3-hydroxy can be replaced with a wide
variety of functional groups. In general, these modifications gener-
ate potent and selective NOP agonists with the exception of 21.
Based on the rapid rat PK data, potent NOP agonists were evaluated
for the antitussive and anxiolytic-like activities.
The in vivo activities of the most potent compound, 24, and
the control compounds, codeine and chlordiazepoxide (CDP), are
presented in Table 7. Compound 24 produces dose-dependent
antitussive and anxiolytic-like activities. It demonstrates superior
activity in animal models of cough and anxiety. The anxiolytic-
like effect of 24 in the rat conditioned lick suppression test can
be attenuated by the NOP antagonist, J-11897, demonstrating that
this effect is mediated by NOP. The pharmacokinetic data col-
lected after dosing at 3 mg/kg in rats are shown in Table 8. Com-
pound 24 is void of enzyme induction in rats and does not inhibit
cytochrome P450 isoforms 2D6 and 3A4. However it shows high
clearance in rats.
a
Activity was determined 2 h after oral dosing.
n = 10 for antitussive and GPPV assay; n = 12–14 for rat CLS assay.
b
hydryl moiety produces potent NOP agonists (Fig. 1). Moving the
substituents from the C-2 to the C-4 position decreases the po-
tency. In general, replacement of the benzhydryl with a benzyl
derivative produces a partial agonist (data not shown). Compared
to 4, the 2,20-dimethyl and 2,20-dichloro analogs (8 and 9) have im-
proved functional activity. The in vitro data and the in vivo inves-
tigation of 8 and 9 are presented in Figure 1 and Table 2.
Compounds 8 and 9 produce dose-dependent antitussive and
anxiolytic-like activity. The antitussive activity of 8 and 9 in the
capsaicin-induced cough model in guinea pigs is attenuated by
the NOP antagonist, J-113397,9 but not the classic opioid receptor
antagonist naltrexone or naloxone, demonstrating that the antitus-
sive activity is mediated by NOP. The anxiolytic-like activity and
side-effect profile of 8 were assessed in a variety of models and dis-
closed recently.8 The specificity of the anxiolytic-like effect of 8 has
also been confirmed with the NOP antagonist, J-113397, and the
opioid receptor antagonist naltrexone.8 Encouraged by the
in vivo activity of 8 and 9, we have further examined the tropane
ring modifications and variations of the C-3 substitution. Since
the methyl groups in 8 were metabolized to the corresponding car-
boxylic acids in rats (Fig. 2), compound 9 was selected for follow-
up studies.
OH
Ph
OH
Ph
in rats
H3C
N
HO2C
N
To determine the potential 3A4 enzyme induction in human,
compound 24 was evaluated in the human pregnane X receptor
(hPXR) reporter gene assay by comparing its activity with the po-
sitive control, rifampicin (RIF). A ratio of induction level relative to
RIF of 0.4 has been set as a practical screening cut-off to minimize
the possibility of generating false positives.10 In this assay 24 dis-
CH3
CO2H
8
8-Met
M+60
Figure 2. Metabolism of 8 in rats.
plays a ratio of 0.89 relative to RIF at 1 lM. The SAR development
to reduce the hPXR activity of 24 is shown in Table 9. In general,
Table 3
Binding affinities of representative axial and equatorial isomers
Table 4
OH
R
Binding affinities of tropane and isotropane derivatives
R
OH
R1
R1
N
OH
R
N
OH
R1
11
R1= Bis(2-chlorophenyl)methyl
12
N
R
R1
N
11
17
R
1 = Bis(2-chlorophenyl)methyl
R
Compds
Kia (nM)
Compds
Kia (nM)
R
Compds
Kia (nM)
Compds
Kia (nM)
NOP
MOP
nd
NOP
MOP
nd
NOP
MOP
NOP
MOP
H
11a
11b
198
12a
12b
1090
N
S
N
11d
3
42
17d
908
7255
19
1487
470
2999
nd
nd
N
N
N
11c
10
12c
3759
11e
7.3
708
17e
385
3586
CH3
Values are means of at least 2–3 experiments (nd = not determined).
a
Values are means of at least 2–3 experiments (nd = not determined).
a

2522
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2519–2523
Table 5
Table 7
Highlights of 3-phenyl modification
Antitussive and anxiolytic-like activity of 24
OH
O
NH2
MW = 465.4, cLogP = 5.4
NOP Ki = 1.7 nM, EC50 = 6 nM
DOP Ki = 2326 nM
KOP Ki = 268 nM
MOP Ki = 38 nM, EC50 = 376 nM
R
R1
N
R1 = Bis(2-chlorophenyl)methyl
R1
N
a
Compds
R
Kia (nM)
EC50 (nM) (Emax)
24
R1 = Bis(2-chlorophenyl)methyl
NOP
MOP
NOP
MOP
a,b
F
Compds
Antitussive activity
ED50 (mg/kg)
Anxiolytic-like activity ED50 (mg/kg)
a,b
11f
2.7
57
16
50
894
GPPV
Rat CLS
24
Codeine
CDP
0.3
6.8
nd
0.4
nd
1.4
nd
N
11g
5.2
13
535
384
1695
N
N
3.2
8.8
a
Activity was determined 2 h after oral dosing (nd = not determined).
n = 10 for antitussive and GPPV assay; n = 12–14 for rat CLS assay.
b
11h
90
(31%)
OMe
11i
11j
1.9
3.6
104
781
16
48
709
netic data collected after dosing at 3 mg/kg in rats are shown in
Table 11. Compared to 24, compound 32 demonstrates an im-
proved pharmacokinetic profile. It exhibits higher exposure, lower
clearance, and improved bioavailability.
O
NH
(60%)
In summary, we have discovered a series of tropane derivatives
as high-affinity ligands for the nociceptin receptor. These com-
pounds produce a full agonist response. Compound 24 demon-
Ph
11k
11l
14
1553
nd
nd
N
H
N
3
622
306
62
nd
(29%)
nd
Table 8
N
Pharmacokinetic data of compound 24
OH
11m
7.4
Rat PK (3 mg/kg, p.o.)
AUC(0–24 h)
Cmax
540 nM h
80 nM
a
Values are means of at least 2–3 experiments (nd = not determined).
t1/2
1.8 h
Bioavailability
Clearance
Vd(ss)
P450 enzyme inhibition (IC50
14-Day rat enzyme Induction
Human hepatocyte clearance
37%
73 mL/min/kg
9.1 L/kg
2D6, 3A4: >30 lM 2C9: 8 lM, 19 M (co, pre)
No issue @ 30 mg/kg
incorporation of a substituent at the para-position of the 3-phenyl
leads to the reduction of the hPXR activity while retaining the anti-
tussive and anxiolytic-like activities, whereas a substituent on the
amide nitrogen increases the hPXR activity. Introduction of a fluo-
rine at the para-position of the 3-phenyl (32) provides a threefold
decrease in the hPXR activity and a tenfold improvement in the
antitussive activity compared to 24 (Table 10). The pharmacoki-
)
3.0
l
L/min/106 cells
Table 9
hPXR activity of C-3 modification analogs
Table 6
H
SAR of representative 3-hydroxy modification analogs
R2
O
N
R
R1
N
R3
Ph
R1
N
R1 = Bis(2-chlorophenyl)methyl
R1 = Bis(2-chlorophenyl)methyl
Compds
R2
R3
Kia (nM)
NOP MOP
hPXR
a
Compds
R
Kia (nM)
EC50 (nM) (% stim. @ 10 lM)
Ratio to RIF (1 lM)
NOP
MOP
NOP
MOP
24
32
33
34
35
36
37
38
39
40
41
42
H
H
H
H
H
H
H
CH3
H
F
Cl
Br
OCH3
OCF3
C(O)NH2
H
H
H
H
H
2
38
126
55
nd
59
nd
nd
50
0.89
0.27
0.05
0.05
0.06
0.10
0.05
1.29
1.49
2.21
2.35
2.38
19
20
21
22
23
24
25
26
27
28
29
30
OCH3
CH2OH
CH2F
CN
CO2H
CONH2
NHCO2CH3
NH2
8
6
636
627
nd
nd
123
38
576
458
27
996
100
601
50
136
nd
nd
nd
6
54
76
nd
35
nd
107
545
2144
nd
nd
nd
376
782
4525
nd
(25%)
nd
16
31
40
22
285
678
4.9
7
3151
100
3
1.7
6
4
2
11
5.3
20
C2H5
215
333
60
NHCONHCH3
NHCO(cPr)
1H-1,2,4-triazol-3-yl)
CH@NOH
CH(CH3)2
CH2CH2OCH3
CH2CH(CH3)OH
10
8.2
11
57
(29%)
a
Values are means of at least 2–3 experiments (nd = not determined).
a
Values are means of at least 2–3 experiments (nd = not determined).

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2519–2523
2523
Table 10
John Hunter, Eric Parker, John Piwinski and Catherine Strader for
helpful discussions.
Antitussive and anxiolytic-like activity of 32
MW = 483.4, cLogP = 5.5
O
NH2
References and notes
NOP
DOP
KOP
MOP
K
K
i = 16 nM, EC50 = 14 nM
i = 1039 nM
R1
N
1. (a) Meunier, J.-C.; Mollereau, C.; Toll, L.; Suaudeau, C.; Moisand, C.; Alvinerie, P.;
Butour, J.-L.; Guillemot, J.-C.; Ferrara, P.; Monsarrat, B.; Mazarguil, H.; Vassart,
G.; Parmentier, M.; Costentin, J. Nature 1995, 377, 532; (b) Reinscheid, R. K.;
Nothacker, H. P.; Bourson, A.; Ardati, A.; Henningsen, R. A.; Bunzow, J. R.;
Grandy, D. K.; Langen, H.; Monsma, F. J., Jr.; Civelli, O. Science 1995, 270, 792.
2. (a) Mollereau, C.; Parmentier, M.; Mailleux, P.; Butour, J.; Moisand, C.; Chalon,
P.; Caput, D.; Vassart, G.; Meunier, J.-C. FEBS Lett. 1994, 341, 33; (b) Fukada, K.;
Kato, S.; Mori, K.; Nishi, M.; Takeshima, H.; Iwabe, N.; Miyata, T.; Houtani, T.;
Sugomoto, T. FEBS Lett. 1994, 343, 42; (c) Chen, Y.; Fan, Y.; Liu, J.; Mestek, A.;
Tian, M.; Kozak, C. A.; Yu, L. FEBS Lett. 1994, 347, 279; (d) Wang, J. B.; Johnson, P.
S.; Imai, Y.; Persico, A. M.; Ozenberger, B. A.; Eppler, C. M.; Uhl, G. R. FEBS Lett.
1994, 348, 75.
3. (a) Mcleod, R. L.; Parra, L. E.; Mutter, J. C.; Erickson, C. H.; Carey, G. J.; Tulshian,
D. B.; Fawzi, A. B.; Smith-Torhan, A.; Egan, R. W.; Cuss, F. M.; Hey, J. Br. J.
Pharmacol. 2001, 132, 1175; (b) Mcleod, R. L.; Bolster, D. C.; Jia, Y.; Parra, L. E.;
Mutter, J. C.; Wang, X.; Tulshian, D. B.; Egan, R. W.; Hey, J. A. Pulmonary
Pharmacol. Ther. 2002, 15, 213; (c) Meunier, J.-C. Exp. Opin. Ther. Patent 2000, 10,
371. and references cited therein; (d) Bignan, G. C.; Connolly, P. J.; Middleton, S.
A. Exp. Opin. Ther. Patents 2005, 15, 357. and references cited therein; (e) Calo,
G.; Guerrini, R.; Rizzi, A.; Salvadori, S.; Regoli, D. Br. J. Pharmacol. 2000, 129,
1261. and references cited therein; (f) Allen, C. N.; Jiang, Z.-G.; Teshima, K.;
Darland, T.; Ikeda, M.; Nelson, C. S.; Quigley, D. I.; Yoshioka, T.; Allen, R. G.; Rea,
M. A.; Grandy, D. K. J. Neurosci. 1999, 19, 2152. and references cited therein; (g)
Teshima, K.; Minoguchi, M. World Patent 2003082333, 2003.
4. (a) Ho, G. D.; Bercovici, A.; Tulshian, D.; Greenlee, W. J.; Fawzi, A.; Smith
Torhan, A.; Zhang, H. Bioorg. Med. Chem. Lett. 2007, 17, 3023; (b) Ho, G. D.;
Bercovici, A.; Tulshian, D.; Greenlee, W. J.; Fawzi, A.; Fernandez, X.; McLeod, R.
L.; Smith Torhan, A.; Zhang, H. Bioorg. Med. Chem. Lett. 2007, 17, 3028.
5. (a) Eyles, D. W.; McLennan, H. R.; Jones, A.; McGrath, J. J.; Stedman, T. J.; Pond, S.
M. Clin. Pharmacol. Ther. 1994, 56, 512; (b) Subramanyam, B.; Rollema, H.;
Woolf, T.; Castagnoli, N. Chem. Biochem. Biophys. Res. Commun. 1990, 166, 238.
6. All new compounds provided satisfactory spectral data along with mass and/or
elemental analysis. Structures of the axial and equatorial isomers were
confirmed by NMR spectroscopic analysis.
K
i = 752 nM
F
K
i = 126 nM, EC50 = 947 nM
32
R1 = Bis(2-chlorophenyl)methyl
a,b
Compds
Antitussive activity
ED50 (mg/kg)
Anxiolytic-like activity ED50 (mg/kg)
a,b
GPPV
0.2
Rat CLS
2.7
32
0.03
a
Activity was determined 2 h after oral dosing.
n = 10 for antitussive and GPPV assay; n = 12–14 for rat CLS assay.
b
Table 11
Pharmacokinetic data of compound 32
Rat PK (3 mg/kg, p.o.)
AUC
1270 nM h
250 nM
1.8 h
45%
33 mL/min/kg
1.8 L/kg
(0–24 h)
Cmax
t1/2
Bioavailability
Clearance
Vd(ss)
strates superior activity in animal models of cough and anxiety to
codeine and chlordiazepoxide. The potential 3A4 enzyme induc-
tion in human has been evaluated in the human pregnane X recep-
tor reporter gene assay.10 Introduction of a fluorine at the para-
position of the 3-phenyl (32) provides a threefold decrease in the
hPXR activity and a tenfold improvement in the antitussive activity
and a better pharmacokinetic profile. Further SAR development on
C-3 has been explored. For instance, the SAR studies of 3-amino-
methyl have been presented recently.11 Other C-3 modifications
will be disclosed in due course.
7. (a) Fawzi, A. B.; Zhang, H.; Weig, B.; Hawes, B.; Graziano, M. P. Eur. J. Pharmacol.
1997, 336, 233; (b) Corboz, M. R.; Rivelli, M. A.; Egan, R. W.; Tulshian, D.;
Matasi, J.; Fawzi, A. B.; Benbow, L.; Smith-Torhan, A.; Zhang, H.; Hey, J. A. Eur. J.
Pharmacol. 2000, 402, 171.
8. Varty, G. B.; Lu, S. X.; Morgan, C. A.; Cohen-Williams, M. E.; Hodgson, R. A.;
Smith-Torhan, A.; Zhang, H.; Fawzi, A. B.; Graziano, M. P.; Ho, G. D.; Matasi, J.;
Tulshian, D.; Coffin, V. L.; Carey, G. J. Pharmacol. Exp. Ther. 2008, 326, 672.
9. Kawamoto, H.; Ozaki, S.; Itoh, Y.; Miyaji, M.; Arai, S.; Nakashima, H.; Kato, T.;
Ohta, H.; Iwasawa, Y. J. Med. Chem. 1999, 42, 5061.
10. (a) Luo, G.; Guenthner, T.; Gan, L.-S.; Humphreys, W. G. Curr. Drug Metab. 2004,
5, 483; (b) Cui, X.; Thomas, A.; Gerlach, V.; White, R. E.; Morrison, R. A.; Cheng,
K.-C. Biochem. Pharmacol. 2008, 76, 680.
Acknowledgments
11. (a) Yang, S.-W.; Ho, G.; Tulshian, D.; Greenlee, W. J.; Fernandez, X.; McLeod, R.
L.; Eckel, S.; Anthes, J. Bioorg. Med. Chem. Lett. 2008, 18, 6340; (b) A manuscript
on C-3 modifications of 24 has been accepted for publication: Yang, S.-W.; Ho,
G.; Tulshian, D.; Greenlee, W. J.; Tan, Z.; Zhang, T.; Smith-Torhan, A.; Fawzi, A.;
Anthes, J.; Lu, S.; Varty, G.; Fernandez, X.; McLeod, R. L.; Hey, J. Bioorg. Med.
Chem. Lett. 2009, 19, 2482.
The authors would like to thank Drs. Ingrid Mergelsberg, Gerald
Werne, and Jesse Wong and their groups for providing the interme-
diate 10; Dr. Tse-Ming Chan and his group for the structure deter-
mination; Drs. Michael Czarniecki, Ashit Ganguly, Guy Higgins,