Spiro-piperidine azetidinones as potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.12.024

A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists. An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to the discovery of a potent antagonist with good

Full text of DOI:10.1016/j.bmcl.2008.12.024

Bioorganic & Medicinal Chemistry Letters 19 (2009) 783–787
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Spiro-piperidine azetidinones as potent TRPV1 antagonists
a
a
a
b
Dong Xiao a, , Anandan Palani , Robert Aslanian , Brian A. McKittrick , Andrew T. McPhail ,
*
Craig C. Correll c, P. Tara Phelps c, John C. Anthes c, Diane Rindgen d
a Chemical Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of Chemistry, P.M. Gross Chemical Laboratory, Duke University, Durham, NC 27708, USA
c Neurobiology Research Department, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
d Exploratory 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:
A series of spiro-piperidine azetidinone were synthesized and evaluated as potential TRPV1 antagonists.
An important issue of plasma stability was investigated and resolved. Further focused SAR study lead to
the discovery of a potent antagonist with good oral pharmacokinetic profile in rat.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 2 October 2008
Revised 3 December 2008
Accepted 4 December 2008
Available online 10 December 2008
Keywords:
TRPV1
Spiro-azetidinone stability
Transient receptor potential V1 (TRPV1) is a membrane-bound,
non-selective, transient receptor potential cation channel. TRPV1 is
expressed throughout the nervous system but is predominantly
expressed in nociceptive C- and Ad-fibers. Data from TRPV1 knock-
out mice and pharmacological evaluation of developed TRPV1
antagonists has demonstrated that TRPV1 is intimately involved
in inflammatory hyperalgesia and detection of noxious stimuli.
Therefore, TRPV1 receptor antagonists may have value in treating
pain, cough and bladder dysfunction.1 Due to its therapeutic poten-
tial, this area of research has attracted intensive interest from a
broad range of academic and industrial research organizations.
Recently, several companies have disclosed their medicinal chem-
istry efforts on TRPV1 antagonists2 and several compounds have
entered the clinic.3
Our exploratory program for TRPV1 antagonists started with an
in-house screening lead 1, a racemic mixture exhibiting moderate
activity.4 Our initial goal of this study was to confirm the lead,
establish the absolute configuration and determine if the TRPV1
activity resided solely in one of the enantiomers (Fig. 1).
The chemistry used in synthesizing compound 1 was adopted
from earlier work in b-lactam chemistry5 and is shown in Scheme
1. The enolate of ester 2 was treated with N-phenylbenzaldimine to
afford a lactam, which was separated by chiral HPLC chromatogra-
phy to enantiomer 3a and 3b in a 1:1 ratio. To elucidate the abso-
lute stereochemistry, 3a was deprotected and treated with (R) or
(S) camphorsulfonyl chloride. As it turned out, only the crystal of
N
IC50 (caps) = 101 10nM
IC50 (PMA) = 113 62nM
O
H
N
N
rat AUC(0-6h,po)@10mpk:
44 ng.h/ml
O
1
Figure 1.
(R) sulfonamide 4 was suitable for X-ray crystallography,6 which
established the absolute stereochemistry of 3a as the (R) configu-
ration. Subsequently, both 3a and 3b were converted separately
to enantiomerically pure 1a and 1b. Between the two enantiomers
only 1b was active. Therefore the active compound 1b had the (S)
configuration. As expected compound 1b was more potent than 1,
however, the AUC in a rat pharmacokinetic (PK) study7 using oral
administration was consistently very low.
After confirmation of the potency and establishment of the
absolute stereochemistry of 1b, the low rat oral pharmacokinetics
was addressed. It was suspected that the spiro-piperidine azetidi-
none core structure may not be stable in plasma under physiolog-
ical pH. It is known that attaching certain strained ring structures
to a b-lactam (such as in penicillins 5) could make the amide car-
bonyl more susceptible to nucleophilic attack.8a On the other hand,
the monocyclic b-lactam core like that found in the commercial
drug ezetimibe (6)8b was not considered to be labile under physi-
ological conditions. To evaluate the stability issue, we synthesized
* Corresponding author. Tel.: +1 908 740 4484.
E-mail address: dong.xiao@spcorp.com (D. Xiao).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.024

784
D. Xiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 783–787
CO2Et
N
Boc
2
1) LHMDS, PhN=CHPh
-78 ºC
N
(S)
N
(R)
+
2) HPLC (Chiralcel OD)
separation
O
O
N
N
Boc
3a
Boc
3b
1) TFA
1) TFA
2) E N, ArNCO
t3
2) E N,
t3
(R)-camphorsulfonyl
chloride
O
S N
O2
N Ph
Ph
N
N
O
+
O
O
4
H
N
H
N
N
N
O
O
1a
1b
IC50 (caps) = 81 3.7 nM
IC50 (PMA)= 43 22 nM
inactive @ 10 μM (caps)
rat. AUC(0-6h,po) @ 10mpk:
19ng.h/ml
Scheme 1.
OH
OH
Ph
O
Ph
Ph
O
Ph
N
Ph
N
H
N
PhHN
HO2C
N
R
N
S
O
N
N
O
F
N
O
Boc
Boc
CO2H
Boc
3
5
6
7
8
F
IR (lactam C=O):
IR (lactam C=O):
IR (lactam C=O):
IR (lactam C=O):
-1
-1
1745cm-1
1780 cm
1739 cm
1764cm-1
Figure 2.
a strained analog 7 as a control to 3. The carbonyl stretches in the
IR spectra of 3 and 7 were determined and compared with the cor-
responding stretch of penicillins and ezetimibe, since the carbonyl
stretch is a well-known measurement of strain in four-membered
rings. As expected, the more strained 7 showed a similar carbonyl
stretch to the penicillins (1764 cmÀ1 vs 1780 cmÀ1), while the less
strained 3 resembled ezetimibe (1745 cmÀ1 vs 1739 cmÀ1). Subse-
quently, the stability was further investigated by treating both 3
and 7 in pH 7.4 buffer spiked with 0.1 M NaSMe and methyl amine
to mimic plasma conditions. Compound 7 quickly degraded to the
corresponding amino acid 8 in 2 h, whereas the less strained com-
pound 3 under identical conditions remained intact for 24 h, mon-
itored by LC–MS. This finding suggested that the low plasma level
of 1b may not be attributed to the stability of the spiro-piperidine-
b-lactam core (Fig. 2).
After confirming the stability of 3 in pH 7.4 buffer, we decided
to investigate the SAR to achieve the following objectives: (1) de-
velop a modular synthetic approach to address the SAR of major
structural components, (2) improve potency to the single digit
nM range and (3) address the inadequate PK profile.
With readily available chiral intermediate 3b in hand, the SAR
of the piperidine urea was investigated first. Based on earlier liter-
ature of urea type TRPV1 antagonists,2t a limited set of analogs
were synthesized using an analogous route to Scheme 1. As shown
in Table 1, the (S) enantiomer of tert-butyl analog 9 displayed low
nanomolar potency, while the (R) enantiomer 10 was much less ac-
tive. Despite the increase in potency, the plasma level of 9 was not
improved. Changing the urea from tert-butylphenyl to tert-buty-
lcyclohexyl afforded a pair of diastereomers 11 and 12. The
trans-isomer 11, while retaining some TRPV1 activity, showed no
plasma levels in a rat PK study. Additional analogs revealed an
improvement in PK when a p-trifluoromethylphenyl urea was
introduced to replace the tert-butyl analog, for example, 14. How-
ever, the potency of analogs 13–15 decreased substantially.
At this time we decided to shift our medicinal chemistry efforts
to other regions of the molecule. One of the initiatives was directed
at the b-lactam chiral center. Having that center present in targets
increased the synthetic complexity and required more resources
and longer timelines to conduct research. We therefore sought to
eliminate the chiral center either by removing the C-linked phenyl
or by transposing it to the ortho-position of the N-aryl phenyl
group. This was the only position the C-linked phenyl can be
accommodated, which renders the molecule achiral. The chemistry
is shown in Scheme 2. Condensation of the enolate of 2 with 2-
bromophenylisocyanate afforded compound 16. Subsequent
reduction of the ester with DIBAL provided compound 17. Cycliza-
tion of 17 under phase-transfer conditions9 provided lactam 18,
which was converted to urea 19 using standard procedures.
Manipulation of the bromide functionality gave rise to targets 20
and 21.

D. Xiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 783–787
785
Table 1
R1
HN R3
N
N
O
O
Entry
R1
R3
IC50 (caps) (nM)
IC50 (PMA) (nM)
12 1.5
rat AUC (0–6 h, po) at 10 mpk ng h/ml
49
9
(S)-Ph
9.4 1.2
10
11
12
13
14
15
(R)-Ph
(S)-Ph
(S)-Ph
(S)-Ph
( )-Ph
( )-Ph
8.5% at 10
49 3.8
528 64
226 53
85 20
lM
ND
ND
0
32 3.1
232 28
ND
ND
ND
1658
ND
Ph
103 60
318 38
CF3
CF3
205 38
N
Br
N
CO2Et
EtO2C CONH
CONH
HO
ClPO(OEt)2
LHMDS
DIBAL
Br
Br
2-BrPhNCO
KOH, PTC
N
N
N
Boc
-78 to 0 ºC
O
-78 ºC
Boc
Boc
N
Boc
18
16
17
2
R
Br
R= H:
H2,P d/C
N
O
N
1) TFA
2) Et3N, ArNCO
O
H
N
H
N
N
N
R= Ph:
PhB(OH)2,K 3PO4
Pd2(dba)3, Sphos
O
O
R= H: 20
R= Ph: 21
19
Scheme 2.
The des-phenyl analog 20 showed a large decrease in activity
compared to 9. Additionally, the phenyl transposed analog 21
was much less active. Retrospectively, when the X-ray structure
of 4 was re-examined, it revealed a phenyl–phenyl edge to face
conformation6 that was not possible for 21 (Table 2).
Unable to simplify the structure by eliminating the b-lactam
chiral center, we shifted the SAR investigation to the lactam N-aryl
moiety. Since electron-deficient heterocycles may be used to re-
place the N-phenyl group to slow down metabolism by oxidative
enzymes, the 2-pyridyl group was introduced. We reasoned that
the 2-pyridyl isomer would be less prone to oxidation than the
3- or 4-substituted analogs due to sterics. This group would also
lower the ClogP and increase aqueous solubility.10 We would re-
tain the p-trifloromethylphenyl as the piperidine urea, since it pro-
vides much desired PK improvement. The synthesis of the
proposed targets is shown in Scheme 3. Once again, the enolate
of 2 was treated with pre-formed N-TMS-benzaldimine, which
afforded unsubstituted lactam 22. A palladium catalyzed arylation
reaction11 provided the N-pyridyl lactam, which was separated to
two enantiomers 23a and 23b. The absolute configurations were
assigned in analogy to the phenyl analogs. Further elaboration fur-
nished targets 24a and 24b.
Table 2
R2
R1
HN
N
N
O
O
Entry
R1
R2
IC50 (caps) (nM)
IC50 (PMA) (nM)
12 1.5
9
20
21
(R)-Ph
H
H
H
H
Ph
9.4 1.2
80 6.2
59
4
73% at 10
l
M
ND

786
D. Xiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 783–787
1) 2-Br-pyridine
Cs2CO3
CO Et
2
1) LHMDS
THF, -78 ºC
HN
Xantphos
2) LHMDS, PhCHO
("PhCHNTMS")
THF, -78 ºC
N
Boc
2
O
Pd2(dba)3
N
2) chiral separation
Boc
22
N
N
N
N
(S)
(R)
+
O
O
N
N
Boc
Boc
23b
23a
1) TFA
2) Et3N, ArNCO
N
N
N
N
(R)
(S)
+
O
O
H
H
N
N
N
N
O
O
CF3
CF3
24b
24a
IC50 (caps) = 83% @ 10 μM
IC50 (caps) = 13 1.1 nM
IC50 (PMA) = 8.5 3.4 nM
rat AUC (0-6 h, po) @ 10mpk:
2500ng.h/ml
iv T1/2 = 2.5 h; BA = 45%
Scheme 3.
S.; Polakowski, J. S.; Marsh, K. C.; Faltynek, C. R.; Lee, C.-H. Bioorg. Med. Chem.
2008, 16, 8516; (b) Blum, C. A.; Zheng, X.; Brielmann, H.; Hodgetts, K. J.;
Bakthavatchalam, R.; Chandrasekhar, J.; Krause, J. E.; Cortright, D.; Matson, D.;
Crandall, M.; Ngo, C. K.; Fung, L.; Day, M.; Kershaw, M.; De Lombaert, S.;
Chenard, B. L. Bioorg. Med. Chem. Lett. 2008, 18, 4573; (c) Cheung, W. S.; Calvo,
R. R.; Tounge, B. A.; Zhang, S.-P.; Stone, D. R.; Brandt, M. R.; Hutchinson, T.;
Flores, C. M.; Player, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 4569; (d) Tamayo,
N.; Liao, H.; Stec, M. M.; Wang, X.; Chakrabarti, P.; Retz, D.; Doherty, E. M.;
Surapaneni, S.; Tamir, R.; Bannon, A. W.; Gavva, N. R.; Norman, M. H. J. Med.
Chem. 2008, 51, 2744; (e) Gomtsyan, A.; Bayburt, E. K.; Schmidt, R. G.; Surowy,
C. S.; Honore, P.; Marsh, K. C.; Hannick, S. M.; McDonald, H. A.; Wetter, J. M.;
Sullivan, J. P.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H. J. Med. Chem. 2008, 51, 392;
(f) Ryu, H.; Jin, M.-K.; Kim, S. Y.; Choi, H.-K.; Kang, S.-U.; Kang, D. W.; Lee, J.;
Pearce, L. V.; Pavlyukovets, V. A.; Morgan, M. A.; Tran, R.; Toth, A.; Lundberg, D.
J.; Blumberg, P. M. J. Med. Chem. 2008, 51, 57; (g) Shishido, Y.; Jinno, M.; Ikeda,
T.; Ito, F.; Sudo, M.; Makita, N.; Ohta, A.; Iki-Taki, A.; Ohmi, T.; Kanai, Y.;
Tamura, T.; Shimojo, M. Bioorg. Med. Chem. Lett. 2008, 18, 1072; (h) Norman, M.
H.; Zhu, J.; Fotsch, C.; Bo, Y.; Chen, N.; Chakrabarti, P.; Doherty, E. M.; Gavva, N.
R.; Nishimura, N.; Nixey, T.; Ognyanov, V. I.; Rzasa, R. M.; Stec, M.; Surapaneni,
S.; Tamir, R.; Viswanadhan, V. N.; Treanor, J. J. S. J. Med. Chem. 2007, 50, 3497;
(i) Drizin, I.; Gomtayan, A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner, R.
J.; DiDomenico, S.; Koenig, J. R.; Turner, S. C.; Jinkerson, T. K.; Brown, B. S.;
Keddy, R. G.; McDonald, H. A.; Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.
M.; Polakowski, J. S.; Segreti, J. A.; Jarvis, M. F.; Faltynek, C. R.; Lee, C.-H. Bioorg.
Med. Chem. 2006, 14, 4740; (j) Ognyanov, V. I.; Balan, C.; Bannon, A. W.; Bo, Y.;
Dominguez, C.; Fotsch, C.; Gore, V. K.; Klionsky, L.; Ma, V. V.; Qian, Y.-X.; Tamir,
R.; Wang, X.; Xi, N.; Xu, S.; Zhu, D.; Gavva, N. R.; Treanor, J. J. S.; Norman, M. H. J.
Med. Chem. 2006, 49, 3719; (k) Fletcher, S. R.; McIver, E.; Lewis, S.; Burkamp, F.;
Leech, C.; Mason, G.; Boyce, S.; Morrison, D.; Richards, G.; Sutton, K.; Jones, A. B.
Bioorg. Med. Chem. Lett. 2006, 16, 2872; (l) Bonache, M. A.; Garcia-Martinez, C.;
Garcia de Diego, L.; Carreno, C.; Perez de Vega, M. J.; Garcia-Lopez, M. T.; Ferrer-
Montiel, A.; Gonzalez-Muniz, R. ChemMedChem 2006, 1, 429; (m) Xi, N.; Bo, Y.;
Doherty, E. M.; Fotsch, C.; Gavva, N. R.; Han, N.; Hungate, R. W.; Klionsky, L.;
Liu, Q.; Tamir, R.; Xu, S.; Treanor, J. J. S.; Norman, M. H. Bioorg. Med. Chem. Lett.
2005, 15, 5211; (n) Suh, Y.-G.; Lee, Y.-S.; Min, K.-H.; Park, O.-H.; Kim, J.-K.;
Seung, H.-S.; Seo, S.-Y.; Lee, B.-Y.; Nam, Y.-H.; Lee, K.-O.; Kim, H.-D.; Park, H.-G.;
Lee, J.; Oh, U.; Lim, J.-O.; Kang, S.-U.; Kil, M.-J.; Koo, J.-Y.; Shin, S. S.; Joo, Y.-H.;
Kim, J. K.; Jeong, Y.-S.; Kim, S.-Y.; Park, Y.-H. J. Med. Chem. 2005, 48, 5823; (o)
Lee, J.; Jin, M.-K.; Kang, S.-U.; Kim, S. Y.; Lee, J.; Shin, M.; Hwang, J.; Cho, S.; Choi,
Y.-S.; Choi, H.-K.; Kim, S.-E.; Suh, Y.-G.; Lee, Y.-S.; Kim, Y.-H.; Ha, H.-J.; Toth, A.;
Pearce, L. V.; Tran, R.; Szabo, T.; Welter, J. D.; Lundberg, D. J.; Wang, Y.; Lazar, J.;
Pavlyukovets, V. A.; Morgan, M. A.; Blumberg, P. M. Bioorg. Med. Chem. Lett.
The pyridyl analog 24b turned out to be potent with equal
activity in the capsaicin and PMA assays. When this compound
was tested in the rat PK assay, a much improved exposure was
achieved with desirable duration. This compound 24b represents
an advanced lead with good potency and oral bioavailability in
rat and is suitable for further in-depth optimization.
In summary, a screening lead 1 was confirmed and preliminary
medicinal chemistry was investigated. During this study, we estab-
lished the absolute stereochemistry of the b-lactam and demon-
strated the importance of a properly substituted phenyl group.
We also confirmed the stability of the center spiro-piperidine-b-
lactam core at physiological pH in the presence of thio and amino
nucleophiles. With a minimum number of analogs, a potent analog
24b with good rat PK profile was discovered. In addition, three syn-
thetic routes were developed, which lay down a solid foundation
for further optimization efforts.
Acknowledgments
We thank Drs. John J. Piwinski and John C. Hunter for support-
ing this research program and Dr. Duane Burnett for helpful
discussions.
References and notes
1. For recent reviews (a) McLeod, R. L.; Correll, C. C.; Jia, Y.; Anthes, J. C. Lung 2008,
186, S59; (b) Gunthorpe, M. J.; Szallasi, A. Curr. Pharm. Des. 2008, 14, 32; (c)
Vasudevan, A.; Kort, M. E. Annu. Rep. Med. Chem. 2007, 42, 81; (d) Westaway, S.
M. J. Med. Chem. 2007, 50, 2589; (e) Correll, C. C.; Palani, A. Expert Opin. Ther.
Patents 2006, 16, 783; (f) Kyle, D. J.; Tafesse, L. Expert Opin. Ther. Patents 2006,
16, 977; (g) Roberts, L. A.; Connor, M. Recent Patents CNS Drug Discov. 2006, 1,
65.
2. For recent example (a) Brown, B. S.; Keddy, R.; Zheng, G. Z.; Schmidt, R. G.;
Koenig, J. R.; McDonald, H. A.; Bianchi, B. R.; Honore, P.; Jarvis, M. F.; Surowy, C.

D. Xiao et al. / Bioorg. Med. Chem. Lett. 19 (2009) 783–787
787
2005, 15, 4143; (p) Lee, J.; Kang, S.-U.; Kil, M.-J.; Shin, M.; Lim, J.-O.; Choi, H.-K.;
Jin, M.-K.; Kim, S. Y.; Kim, S.-E.; Lee, Y.-S.; Min, K.-H.; Kim, Y.-H.; Ha, H.-J.; Tran,
R.; Welter, J. D.; Wang, Y.; Szabo, T.; Pearce, L. V.; Lundberg, D. J.; Toth, A.;
Pavlyukovets, V. A.; Morgan, M. A.; Blumberg, P. M. Bioorg. Med. Chem. Lett.
2005, 15, 4136; (q) Shao, B.; Huang, J.; Sun, Q.; Valenzano, K. J.; Schmid, L.;
Nolan, S. Bioorg. Med. Chem. Lett. 2005, 15, 719; (r) Gomtsyan, A.; Bayburt, E. K.;
Schmidt, R. G.; Zheng, G. Z.; Perner, R. J.; Didomenico, S.; Koenig, J. R.; Turner,
S.; Jinkerson, T.; Drizin, I.; Hannick, S. M.; Macri, B. S.; McDonald, H. A.; Honore,
P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.; Stewart, K. D.; Oie, T.; Jarvis, M. F.;
Surowy, C. S.; Faltynek, C. R.; Lee, C. H. J. Med. Chem. 2005, 48, 744; (s) Doherty,
E. M.; Fotsch, C.; Bo, Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han, N.; Kelly, M.
G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang, X.; Zhu, J.;
Norman, M. H. J. Med. Chem. 2005, 48, 71; (t) Swanson, D. M.; Dubin, A. E.; Shah,
C.; Nasser, N.; Chang, L.; Dax, S. L.; Jetter, M.; Breitenbucher, J. G.; Liu, C.; Mazur,
C.; Lord, B.; Gonzales, L.; Hoey, K.; Rizzolio, M.; Bogenstaetter, M.; Codd, E. E.;
Lee, D. H.; Zhang, S.-P.; Chaplan, S. R.; Carruthers, N. I. J. Med. Chem. 2005, 48,
1857. and references cited therein.
6. The X-ray coordinates of compound 4 has been deposited with Cambridge
Crystallographic Data Centre for small molecules (CCDC) as CCDC 708149. The
ORTEP diagram of 4 (40% probability ellipsoids) is shown below:
O
S
N
N Ph
Ph
O2
O
4
3. Szallasi, A.; Cortwright, D. A.; Blum, C. A.; Eid, S. R. Nat. Rev. Drug Discov. 2007,
6, 357.
4. TRPV1 assay: TRPV1 activity was determined via FLIPR assay at 37 °C using a
stably transfected HEK293 cell line. All compounds used in these studies
were dissolved in dimethyl sulfoxide (DMSO) and vehicle alone (DMSO) was
used as a control. In all experiments, DMSO concentration was kept below
0.2% final. All compounds were characterized by their ability to inhibit 2
modes of TRPV1 activation: (1) small molecule induced activation via the
addition of capsaicin (caps), and (2) phosphorylation-mediated activation of
TRPV1 through activation of PKC via the addition of phorbol myristate
acetate (PMA). Calculation of EC50 and IC50 values were determined using
GraphPad Prism v3.02 (GraphPad Software, Inc.). Data presented is the
average of at least three separate determinations. All values are given in nM
and SEM given for each compound except for the less potent compounds, for
which only % inhibition are reported. Full experimental details: Correll, C. C.;
Phelps, P. T.; Anthes, J. C.; Egan, R. W.; Umland, S.; Greenfeder, S. Neurosci.
Lett. 2004, 370, 55.
7. The rat PK assay was run at 10 mpk using oral dosing with 20% HPBCD as
vehicle. AUC was determined from 0 to 6 hours. For lead compound 24b, an
additional iv dosing was performed. Reference: Cox, K. A.; Dunn-Meynell, K.;
Korfmacher, W. A.; Broske, L.; Nomeir, A. A.; Lin, C. C.; Cayen, M. N.; Barr, W. H.
Drug Discov. Today 1999, 4, 232.
8. For a discussion on the influence of bicyclic structure on susceptibility of
nucleophilic attack towards lactam carbonyls in drug design: (a) Smith, P. W.;
Whittington, A. R.; Cobley, K. N.; Jaxa-Chamiec, A.; Finch, H. J. Chem. Soc., Perkin
Trans. I 2001, 1, 21; (b) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R.;
Yumube, N.; Clader, J. W.; Burnett, D. A. J. Med. Chem. 1988, 41, 973.
9. (a) Thiruvengadam, T. K.; Tann, C. H.; Lee, J.; McAllister, T. L.; Sudhakar, A. US
patent 1994, 5306817.; (b) Wu, G.; Tormos, W. J. Org. Chem. 1997, 62, 6412.
10. The values of CLogP and solubility of 9 and its pyridyl analog 24b calculated by
ACDLABS 11.0 (Ó Advanced Chemistry Development, Inc., Toronto, Canada) are
shown below: 9: CLogP: 5.11; solubility at pH 7: 9.4 Â 10À8 mol/L 24b: CLogP:
4.48; solubility at pH 7: 3.0 Â 10À7 mol/L.
5. Aslanian, R. G.; Chan, T.-Y.; Harris, J. M.; McKittrick, B. A.; Neustadt, B. R.;
Palani, A.; Priestley, T.; Smith, E. M.; Stamford, A. W.; Vaccaro, H. M.; Xiao, D.
Preparation of spirocyclic azetidinone derivatives and therapeutic applications
thereof PCT Int. Appl. 2008, WO 2008033465 A1.
11. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.