Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1- methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity

Article abstract of DOI:10.1021/jm060996+

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Full text of DOI:10.1021/jm060996+

7584
J. Med. Chem. 2006, 49, 7584-7587
Letters
Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2-
(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-
{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide
(MK-0364), a Novel, Acyclic Cannabinoid-1
Receptor Inverse Agonist for the Treatment of
Obesity
Figure 1. Structures of SR141716 and SLV319.
Linus S. Lin,*,† Thomas J. Lanza, Jr.,† James P. Jewell,†
Ping Liu,† Shrenik K. Shah,† Hongbo Qi,† Xinchun Tong,†
Junying Wang,† Suoyu S. Xu,† Tung M. Fong,§
Chun-Pyn Shen,§ Julie Lao,§ Jing Chen Xiao,§
Lauren P. Shearman,∞ D. Sloan Stribling,∞
Kimberly Rosko,∞ Alison Strack,∞ Donald J. Marsh,§
Yue Feng,§ Sanjeev Kumar,‡ Koppara Samuel,‡ Wenji Yin,‡
Lex H. T. Van der Ploeg,§,# Mark T. Goulet,†,# and
William K. Hagmann†
Figure 2. Racemic 1 was separated into slower eluting (S,S)-
enantiomer 2 and faster eluting (R,R)-enantiomer 3.
active (CB1R IC50 ) 95 ( 23 nM). The more potent enantiomer
3 demonstrated good pharmacokinetic properties in the rat (1
mg/kg iv, 2 mg/kg po, F ) 68%, t1/2 ) 2 h). However, when
evaluated in the diet-induced obese (DIO) rat model, 3 (up to
10 mg/kg po) showed no significant effects on overnight food
intake or body weight reduction, thereby setting the stage for
lead optimization.
Departments of Medicinal Chemistry, Metabolic Disorders,
Pharmacology, and Drug Metabolism, Merck Research
Laboratories, Rahway, New Jersey 07065
ReceiVed August 17, 2006
Abstract: The discovery of novel acyclic amide cannabinoid-1 receptor
inverse agonists is described. They are potent, selective, orally
bioavailable, and active in rodent models of food intake and body weight
reduction. A major focus of the optimization process was to increase
in vivo efficacy and to reduce the potential for formation of reactive
metabolites. These efforts led to the identification of compound 48 for
development as a clinical candidate for the treatment of obesity.
After a thorough investigation of the backbone scaffold of 1
that did not yield any significant improvements in potency,
further efforts focused on varying the substituents of the two
aromatic rings of the amine fragment. The synthetic route began
with substituted phenyl acetates 4 (Scheme 1). Base-catalyzed
alkylation with benzyl halides was followed by conversion to
the Weinreb amide 6. Reaction of 6 with methyl Grignard
reagent afforded ketone 7. Reduction of 7 was accomplished
with sodium borohydride or lithium tri(sec-butyl)borohydride
to afford 8 as the major diastereomer.7 The reduction with
sodium borohydride was generally less diastereoselective (4:1)
than with tri(sec-butyl)borohydride (>10:1). The resulting
secondary alcohol 8 was converted to the amine 9, which was
subsequently coupled to a fibric acid to give the anti-diaste-
reomer 10 as the major product in racemic form. The less
selective borohydride reduction provided a useful amount of
the minor syn-diastereomers of 10 for structure-activity-relation-
ship (SAR) comparisons.
The individual enantiomers of 10d were prepared by an
enantiospecific route (Scheme 2), starting from (1R,2R)- or
(1S,2S)-1-phenylpropylene oxide (11 or 12).7 Epoxide opening
with 4-chlorobenzylmagnesium chloride afforded the secondary
alcohols (S,R)-13 and (R,S)-14, respectively, which were
separately converted to the amines (S,S)-15 and (R,R)-16 and
subsequently to the amides 17 and 18.
With the enantiomerically pure amines 15 and 16 in hand,
the SAR of the aromatic ring of the acid moiety was then
addressed. The synthesis of the acid fragments followed several
different routes (Scheme 3). The first route was a one-step
reaction between 1,1,1-trichloro-tert-butanol 19 and a substituted
phenol 20 to afford fibrate 21.8 Since hydroxypyridines were
generally poor substrates for this reaction, an alternative route
was developed. Reaction of 2- or 3-hydroxypyridine (23, 24)
with benzyl lactate 22 under Mitsunobu conditions afforded
Obesity is a serious and chronic medical condition that is
rapidly growing throughout the world. In many cases, the
excessive body weight is the root cause of subsequent comor-
bidities, including diabetes, hypertension, cardiovascular disease,
cancer, and arthritis.1 Although lifestyle modifications may be
the preferred approach for the management of obesity, it is often
insufficient or unsustainable. Therefore, new anti-obesity thera-
peutics are actively pursued. The involvement of the cannabinoid
receptor system in regulating feeding behavior has been
demonstrated in animal and clinical studies.2,3 Several canna-
binoid-1 receptor (CB1R) inverse agonists including SR141716
(rimonabant)4 and SLV3195 (Figure 1) have been reported to
be efficacious in various models of feeding behavior, and
rimonabant has been approved in the EU for the treatment of
obesity. Herein, the discovery of novel, acyclic CB1R inverse
agonists is described.
Our efforts started with a screening lead (1) that was
determined to be a racemic mixture of the anti-diastereomers6
(Figure 2). Preparative chiral HPLC separation afforded the
(S,S)-isomer 2 and the (R,R)-isomer 3. The stereochemical
assignments were established by X-ray analysis. The racemate
of the syn-diastereomers of 1 was synthesized and was less
* To whom correspondence should be addressed. Phone: 732-594-8391.
Fax: 732-594-5966. E-mail: linus_lin@merck.com.
† Department of Medicinal Chemistry.
§ Department of Metabolic Disorders.
∞ Department of Pharmacology.
‡ Department of Drug Metabolism.
# Current affiliation: MRL Boston.
10.1021/jm060996+ CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/21/2006

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7585
Scheme 4a
Scheme 1a
a (a) Y-PhCH2Br, KHMDS, -78 °C f room temp; (b) MeONH(Me)‚HCl,
Me2AlCl, room temp; (c) MeMgCl, ether, 0 °C; (d) NaBH4, MeOH or
LiBH(sec-Bu)3, THF, -78 °C; (e) MsCl, Et3N; (f) NaN3, DMF, 100 °C;
(g) H2, Boc2O, PtO2 (cat.), EtOAc; (i) HC/dioxane, EtOAc; (j) fibric acid,
(COCl)2, then N-methylmorpholine, CH2Cl2.
a (a) Cs2CO3, CH3CN, 50 °C; (b) NaOH, H2O/MeOH; (c) PyBop,
N-methylmorpholine, CH2Cl2, room temp; (d) Scheme 1, steps e-g; (e)
Zn(CN)2, Pd2(dba)3, dppf, DMF/H2O (98:2), 100 °C; (f) HCl/dioxane,
EtOAc.
Scheme 2a
another procedure was investigated. Protection of the pyridine
nitrogen with a SEM group provided 32, which was reacted
with benzyl lactate O-triflate to yield the desired O-alkylation
product. The SEM group was cleaved upon workup to give 33,
which was converted to acid 34 under standard conditions. These
new acids were then coupled to amine 15 to give the desired
amides (35a-h).
Further optimization resulted in a two-step synthesis of
pyridine acids 41 and 42 (Scheme 4). Reaction of appropriately
substituted 2-hydroxypyridines with R-bromoisobutyrate in the
presence of cesium carbonate afforded the esters 39 and 40,
which were hydrolyzed to acids 41 and 42. Coupling of these
acids with the (S,S)-amine 15 provided amides 43 and 44. The
bromo-substituted amine 46 was converted to the cyano amine
47 under palladium-catalyzed cyanation conditions.9 Amide
coupling with acid 42 followed by HPLC on a chiral column
afforded the more potent (S,S)-isomer 48.10
a (a) 4-ClPhCH2MgCl, 0 °C; (b) Scheme 1, steps e-i; (c) fibric acid,
(COCl)2, then N-methylmorpholine, CH2Cl2.
Scheme 3a
Inhibition data of [3H]CP-55940 binding to recombinant
human CB1R and CB2R expressed in CHO cells are sum-
marized in Table 1. The anti-diastereomers were generally 2-
to 10-fold more potent than the syn-diastereomers, so only the
data for the anti-diastereomers are listed. Deletion of the
4-chloro substituent from phenyl ring A in 10d resulted in an
increase in binding affinity, whereas replacement with fluorine
resulted in a loss of potency (10a). Fluorine substitution at the
2-position had little effect (10c), but substitution at the 3-position
enhanced potency (10b). For phenyl ring B, the 4-substituent
was required for optimal potency (10d,f,g vs 10h). Substitution
at the 2-position resulted in significant loss of binding activity
(10e). It is interesting that whereas the more potent enantiomer
of 1 is 3 with the (2R,3R)-configuration, the more potent
enantiomer of 10d is 17 with the (2S,3S)-configuration.
Employing the potency enhancing substitution pattern on the
amine fragment found in 10d (17), the SAR of the aryloxy group
was then explored (Table 2). Both 4- and 3-substitutions on
the phenyl ring of the acid moiety were tolerated and were
preferred over 2-substitution. The 3,5-difluoro analogue 35e is
among the more potent compounds. In addition, replacement
of the phenyl ring with a 2-pyridyl group was well tolerated
(35f), although the regioisomeric 3- or 4-pyridyl groups were
less favorable (35g and 35h). Compound 35e was also found
a (a) NaOH, acetone; (b) DEAD, Ph3P, CH2Cl2; (c) KHMDS, MeI, THF,
-78 °C; (d) H2, Pd/C (cat.), MeOH; (e) SEMCl; (f) BnO2CCH(Me)OTf,
60 °C.
esters 25 and 26 along with some N-alkylated side products.
Methylation of 25 and 26 followed by hydrogenolysis afforded
acids 29 and 30. Because 4-hydroxypyridine (31) afforded the
N-alkylated product exclusively under Mitsunobu conditions,

7586 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Letters
Table 1. Inhibition of CB1R and CB2R (IC50, nM)a by Substituted
Table 3. Covalent Binding to Human Liver Microsomal Proteins
Amidesb
Obtained by Incubation of Tritiated Compounds13
compd
bindinga
35c
35e
35f
43
3900 ( 300
1700 ( 320
910 ( 110
300 ( 81
88 ( 4
compd
X
Y
CB1R IC50, nM
CB2R IC50, nM
44
48 (MK-0364)
27 ( 2
1
4-Cl
4-Cl
4-Cl
4-F
3-F
2-F
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
2-Cl
4-CF3
4-F
20 ( 12
48 ( 17
13 ( 6
1100 ( 1100
>2000
a pmol equiv/mg protein at 1 h of incubation.
(S,S)-2
(R,R)-3
10a
10b
10c
10d
10e
10f
10g
600 ( 200
90 ( 4
MS pattern suggested that the covalent linkage was formed
between the 3,5-difluorophenoxy fragment of 35e and the
sulfhydryl group of glutathione. Presumably, the electron-rich
phenyl ring was oxidized to a putative arene oxide intermediate
that then reacted with glutathione or nucleophilic species on
microsomal proteins, resulting in formation of covalent adducts.
The mechanism of bioactivation for 35e was believed to be
oxidation of the electron rich aryloxy group, so a more electron-
deficient aryl group would be expected to be less prone to such
metabolic activation. Indeed, 35f was found to have reduced
levels of covalent binding (910 pmol equiv/mg protein) when
the 3,5-difluorophenyl ring was replaced with the more electron-
deficient 2-pyridyl ring (Table 3).13 Further reduction of
bioactivation was accomplished by introduction of an electron-
withdrawing substituent such as a 5-chlorine (3-fold) or 5-tri-
fluoromethyl group (10-fold). The addition of the 5-trifluorom-
ethyl group (44) also improved potency and selectivity relative
to the unsubstituted pyridine derivative 35f. The residual
covalent binding in 44 (88 pmol equiv/mg protein) was thought
to result from the bioactivation of the unsubstituted phenyl ring
A. Substitution of ring A with an electron-withdrawing group
was sought to further reduce the potential for bioactivation. This
effort was highlighted by the incorporation of a cyano substitu-
ent, which afforded a CB1R inverse agonist (48, MK-0364) with
minimal potential for covalent protein binding.
Compound 48 was an exceptionally potent and selective (900-
fold over CB2) CB1R inverse agonist with >500-fold improve-
ment in affinity over the original lead (1). In a functional assay
of cyclic-AMP production, 48 was determined to be an inverse
agonist (EC50 ) 2.4 ( 1.4 nM, -123% maximal activation;
relative to CP-55940). Compound 48 also had a good pharma-
cokinetic profile in three species (rat, 1 mg/kg iv, 2 mg/kg po,
F ) 74%, t1/2 ) 2.7 h; dog, 0.2 mg/kg iv, 0.4 mg/kg po, F )
31%; t1/2 ) 14 h; rhesus monkey, 0.2 mg/kg iv, 0.4 mg/kg po,
F ) 31%, t1/2 ) 3.6 h) and good brain exposure (1 mg/kg iv,
brain and plasma concentrations of 0.11 and 0.18 µM at 1 h,
respectively).
The in vivo activity of 48 was first assessed with a rat
hypothermia model. In this model, a rapid 4-5 °C decrease in
body temperature was first induced by CB1R agonist CP-55940.
Administration of 48 (3 mg/kg iv) completely blocked the
temperature decrease (P < 0.00001 vs vehicle), consistent with
total in vivo inhibition of the CB1 receptors.14 The effects of
48 on feeding behavior were evaluated in the DIO rat model.
After 14 days of treatment at 0.3, 1, and 3 mg/kg (po, qd), a
sustained and dose-dependent reduction relative to the vehicle-
treated animals in body weight (4 ( 1%, 5 ( 1%, and 7 ( 1%,
respectively; P < 0.05) was observed.14 The effects on food
intake and body weight were shown to be mediated by CB1R
by the lack of such effects in Cnr1 knockout mice.14 More
details of the in vivo pharmacology of 48 will be reported in
future publications.14
2.8 ( 0.8
12 ( 3
530 ( 6
410 ( 130
610 ( 370
2.5 ( 1.1
140 ( 25
3.4 ( 1.4
14 ( 0.6
33 ( 0.3
3.0 ( 1.2
170 ( 110
6.1 ( 2.5
17 ( 8
10h
H
4-Cl
4-Cl
(S,S)-17
(R,R)-18
SR141716
SLV319
H
H
770 ( 620
1700 ( 700
600 ( 650
1100 ( 200
a Inhibition of binding (mean ( SD) (n g 2 independent experiments).11
b Racemic mixture of the anti-diastereomers except as noted.
Table 2. Inhibition of CB1R and CB2R (IC50, nM)a by Substituted
Amidesb
compd
X
Ar
CB1R IC50, nM
CB2R IC50, nM
17a
35a
35b
35c
35d
35e
35f
35g
35h
43
H
4-Cl-Ph
3-Cl-Ph
2-Cl-Phc
Ph
3.0 ( 1.2
1.5 ( 0.5
18 ( 4
770 ( 620
190 ( 80
H
H
H
H
H
H
H
H
H
H
CN
2.0 ( 1.4
1.6 ( 0.8
1.1 ( 1.0
1.8 ( 1.4
19 ( 3
450 ( 180
290 ( 60
200 ( 110
88 ( 28
3-F-Ph
3,5-F2-Ph
2-pyr
3-pyrc
4-pyrc
17 ( 1
1200 ( 300
100 ( 20
140 ( 20
290 ( 60
5-Cl-2-pyr
5-CF3-2-pyr
5-CF3-2-pyr
1.3 ( 0.3
0.5 ( 0.2
0.3 ( 0.1
44
48
a Inhibition of binding (mean ( SD) (n g 2 independent experiments).11
b (S,S)-Enantiomer. c Racemic mixture of anti-diastereomers.
to have good pharmacokinetic properties (1 mg/kg iv, 2 mg/kg
po, F ) 19%, t1/2 ) 2.4 h) and brain exposure (1 mg/kg iv,
brain and plasma concentrations of 0.27 and 0.35 µM at 1 h,
respectively) in the rat. In contrast to 3, 35e was highly
efficacious in the DIO rat model, resulting in dose-dependent
reduction in overnight food intake (-55 ( 2% and -81 ( 6%
at 3 and 10 mg/kg po, respectively; P < 0.05 vs vehicle at both
doses).
Formation of reactive metabolites and subsequent covalent
modifications of proteins are implicated in cases of allergic and/
or idiosyncratic immune-mediated toxicities.12 Because such
toxicities may not manifest themselves until the later stages of
development or after marketing, bioactivation should be mini-
mized in drug candidates. Compound 35e was evaluated for
the potential of reactive metabolite formation. Tritiated 35e was
incubated with human and rat liver microsomes and afforded
very high levels of irreversible binding of radioactivity (1700
pmol equiv./mg protein).13 When the incubation was performed
with glutathione as an additive, covalent adducts of 35e with
glutathione were detected by LC-MS. Careful analysis of the
In summary, we have discovered a series of novel, acyclic
CB1R inverse agonists that are potent, selective, and orally

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7587
1,8-naphthyidinones and their evaluation as novel, orally active CB1
receptor inverse agonists. Bioorg. Med. Chem. Lett. 2006, 16, 681-
685. (d) Plummer, C. W.; Finke, P. E.; Mills, S. G.; Wang, J.; Tong,
X.; Doss, G. A.; Fong, T. M.; Lao, J. Z.; Schaeffer, M.-T.; Chen, J.;
Shen, C.-P.; Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Van
der Ploeg, L. H. T. Synthesis and activity of 4,5-diarylimidazoles as
human CB1 receptor inverse agonists. Bioorg. Med. Chem. Lett. 2005,
15, 1441-1446.
bioavailable. A major focus of the optimization effort was to
increase in vivo efficacy and to attenuate the potential for bioac-
tivation of the initial lead. These compounds are active in models
of feeding behavior and hypothermia, and 48 (MK-0364) is cur-
rently undergoing clinical evaluation for the treatment of obesity.
Acknowledgment. We acknowledge the contributions of Ms.
Nancy Tsou, Dr. Richard Ball, Dr. David Mathre, Ms. Dorothy
Levorse, Dr. Karen Owens, and many members of the Labora-
tory of Animal Resources.
(6) The synthesis and stereochemical assignment of this amine have been
reported: (a) Schultz, E. M.; Bolhofer, W. A.; Augenblick, A.;
Bicking, J. B.; Habecker, C. N.; Horner, J. K.; Kwong, S. F.;
Pietruszkiewcz, A. M. Maleamic acids that affect plasma cholesterol
and penicillin excretion. J. Med. Chem. 1967, 10, 717-724. (b) Pines,
H. S.; Chemerda, J. M.; Kozlowski, M. A.; Weinstock, L. M.; Davis,
P.; Handelsman, B.; Grenda, V. J.; Lindberg, G. W. The stereo-
chemistry of 2,3-diphenyl-1-methylpropylamine. J. Med. Chem. 1967,
10, 725-728.
Supporting Information Available: Experimental details and
elemental analysis results. This material is available free of charge
via the Internet at http://pubs.acs.org.
(7) Iwasawa, Y.; Shibata, J.; Nonoshita, K.; Arai, S.; Masaki, H.;
Tomimoto, K. Stereoselective synthesis of J-104,118 and J-104,123,
novel, potent inhibitors of squalene synthase. Tetrahedron 1996, 52,
13881-13894.
(8) Corey, E. J.; Barcza, S.; Klotmann, G. Directed conversion of the
phenoxy grouping into a variety of cyclic polyfunctional systems. J.
Am. Chem. Soc. 1969, 91, 4782-4786.
(9) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. A highly catalytic
robust palladium catalyzed cyanation of aryl bromides. Tetrahedron
Lett. 1999, 40, 8193-8195.
(10) The stereochemistry of 36 was confirmed by X-ray analysis. Also
see: Burns, D. H.; Chen, A. M.; Gibson, R. E.; Goulet, M. T.;
Hagmann, W. K.; Hamill, T. G.; Jewell, J. P.; Lin, L. S.; Liu, P.;
Peresypkin, A. V. Radiolabeled cannabinoid-1 receptor modulators.
PCT Patent Application WO2005/009479A1, 2005.
(11) (a) Shen, C.-P.; Xiao, J. C.; Armstrong, H.; Hagmann, W.; Fong, T.
M. F200A substitution in the third transmembrane helix of human
cannabinoid CB1 receptor converts AM2233 from receptor agonist
to inverse agonist. Eur. J. Pharmacol. 2006, 531, 41-46. (b) Felder,
C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.; Mackie, K.; Blond,
O.; Lai, Y.; Ma, A. L.; Mitchell, R. L. Comparison of the
pharmacology and signal transduction of the human cannabinoid CB1
and CB2 receptors. Mol. Pharmacol. 1995, 48, 443-450.
(12) (a) Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A.
Drug-protein adducts: an industry perspective on minimizing the
potential for drug bioactivation in drug discovery and development.
Chem. Res. Toxicol. 2004, 17, 3-16. (b) Nassar, A. F.; Lopez, A.
A. Strategies for dealing with reactive intermediates in drug discovery
and development. Curr. Opin. Drug DiscoVery DeV. 2004, 7, 126-
136.
(13) Samuel, K.; Yin, W.; Stearns, R. A.; Tang, Y. S.; Chaudhary, A. G.;
Jewell, J. P.; Lanza, T., Jr.; Lin, L. S.; Hagmann, W. K.; Evans, D.
C.; Kumar, S. Addressing the metabolic activation potential of new
leads in drug discovery: a case study using ion trap mass spectrom-
etry and tritium labeling techniques. J. Mass Spectrom. 2003, 38,
211-221.
References
(1) Olshansky, S. J.; Passaro, D. J.; Hershow, R. C.; Layden, J.; Carnes,
B. A.; Brody, J.; Hayflick, L.; Butler, R. N.; Allison, D. B.; Ludwig,
D. S. A potential decline in life expectancy in the United States in
the 21st century. New Engl. J. Med. 2005, 352, 1138-1145.
(2) Pertwee, R. G. Cannabinoid receptor ligands: clinical and neuro-
pharmalogical considerations relevant to future drug discovery and
development. Expert Opin. InVest. Drugs 2000, 9, 1553-1571.
(3) (a) Smith, R. A.; Fathi, Z. Recent advances in the research and
development of CB1 antagonists. IDrugs 2005, 8, 53-66. (b) Lange,
J. H. M.; Kruse, C. G. Medicinal chemistry strategies to CB1
cannabinoid receptor antagonists. Drug DiscoVery Today 2005, 10,
693-702.
(4) (a) Sorbera, L. A.; Castaner, J.; Silvestre, J. S. Rimonabant
hydrochloride. Drugs Future 2005, 30, 128-137. (b) Van Gaal, L.
F. Rissanen, A. M.; Scheen, A. J.; Ziegler, O.; Rossner, S. Effects
of the cannabinoid-1 receptor blocker rimonabant on weight reduction
and cardiovascular risk factors in overweight patients: 1-year
experience from the RIO-Europe study. Lancet 2005, 365, 1389-
1397.
(5) Lange, J. H. M.; Coolen, H. K. A. C.; van Stuivenberg, H. H.;
Dijksman, J. A. R.; Herremans, A. H. J.; Ronken, E.; Keizer, H. G.;
Tipker, K.; McCreary, A. C.; Veerman, W.; Wals, H. C.; Stork, B.;
Verveer, P. C.; den Hartog, A. P.; de Jong, N. M. J.; Adolfs, T. J.
P.; Hoogendoorn, J.; Kruse, C. G. Synthesis, biological properties,
and molecular modeling investigations of novel 3,4-diarylpyrazolines
as potent and selective CB1 cannabinoid receptor antagonists. J. Med.
Chem. 2004, 47, 627-643. Recent reports of other selective CB1
inverse agonists: (a) Muccioli, G. G.; Wouters, J.; Charlier, C.;
Scriba, G. K. E.; Pizza, T.; Pace, P. D.; Martino, P. D.; Poppitz, W.;
Poupaert, J. H.; Lambert, D. M. Synthesis and activity of 1,3,5-
triphenylimidazolidine-2,4-diones and 1,3,5-triphenyl-2-thioxoimi-
dazolin-4-ones: characterization of new CB1 cannabinoid receptor
inverse agonists/antagonists. J. Med. Chem. 2006, 49, 872-882; (b)
Carpino, P. A.; Griffith, D. A.; Sakya, S.; Dow, R. L.; Black, S. C.;
Hadcock, J. R.; Iredale, P. A.; Scott, D. O.; Fichtner, M. W.; Rose,
C. R.; Day, R.; Dibrino, J.; Butler, M.; DeBartolo, D. B.; Dutcher,
D.; Gautreau, D.; Lizanao, J. S.; O’Connor, R. E.; Sands, M. A.;
Kelly-Sullivan, D.; Ward, K. M. New bicyclic cannabinoid receptor-1
(CB1-R) antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 731-736.
(c) Debenham, J. S.; Madsen-Duggan, C. B.; Walsh, T. F.; Wang,
J.; Tong, X.; Doss, G. A.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.;
Xiao, J. C.; Huang, C. R,-R. C.; Shen, C.-P.; Feng, Y.; March, D. J.;
Stribling, D. S.; Shearman, L. P.; Strack, A. M.; MacIntyre, D. E.;
Van der Ploeg, L. H. T.; Goulet, M. T. Synthesis of functionalized
(14) Fong, T. M.; Guan, X.-M.; Marsh, D. J.; Shen, C.-P.; Stribling, D.
S.; Rosko, K. M.; Lao, J.; Yu, H.; Feng, Y.; Xiao, J. C.; Van der
Ploeg, L. H. T.; Goulet, M. T.; Hagmann, W. K.; Lin, L. S.; Lanza,
T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang,
J.; Xu, S. S.; Francis, B.; Strack, A. M.; MacIntyre, D. E.; Shearman,
L. P. Anti-obesity efficacy of a novel cannabinoid-1 receptor inverse
agonist MK-0364 in rodents. J. Pharmacol. Exp. Ther., submitted
for publication.
JM060996+