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

Journal of Medicinal Chemistry

Volumn 49, Issue 26, 2006, Pages 7584-7587

  Lin, Linus S ^a   Lanza Jr , Thomas J ^a   Jewell, James P ^a   Liu, Fing ^a   Shah, Shrenik K ^a   Qi, Hongbo ^a   Tong, Xinchun ^a   Wang, Junying ^a   Xu, Suoyu S ^a   Fong, Tung M ^a   Shen, Chun Pyn ^a   Lao, Julie ^a   Xiao, Jing Chen ^a   Shearman, Lauren P ^a   Stribling, D Sloan ^a   Rosko, Kimberly ^a   Strack, Alison ^a   Marsh, Donald J ^a   Feng, Yue ^a   Kumar, Sanjeev ^a   Samuel, Koppara ^a   Yin, Wenji ^a   Van Der Ploeg, Lex H T ^a,b   Goulet, Mark T ^a,b   Hagmann, William K ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b MRL Boston ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; CANNABINOID 1 RECEPTOR INVERSE AGONIST; CANNABINOID RECEPTOR AGONIST; MK 0364; MK 064; N [3 (4 CHLOROPHENYL) 2 (3 CYANOPHENYL) 1 METHYLPROPYL] 2 METHYL 2 [[5 (TRIFLUOROMETHYL)PYRIDIN 2 YL]OXY]PROPANAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DISEASE MODEL; DRUG BIOAVAILABILITY; DRUG DOSE COMPARISON; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HYPOTHERMIA; NONHUMAN; OBESITY; PROCESS OPTIMIZATION; RACEMIZATION; RAT; REACTION ANALYSIS; STRUCTURE ANALYSIS;

ANIMALS; ANTI-OBESITY AGENTS; BODY WEIGHT; CANNABINOIDS; CYCLIC AMP; EATING; HUMANS; LIVER; MICROSOMES; OBESITY; RATS; RECEPTOR, CANNABINOID, CB1; RECEPTOR, CANNABINOID, CB2;

EID: 33845950577     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060996+     Document Type: Article

References (23)

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 neuropharmalogical considerations relevant to future drug discovery and development. Expert Opin. Invest. Drugs 2000, 9, 1553-1571.
3. 1 antagonists. IDrugs 2005, 8, 53-66.
4. 1 cannabinoid receptor antagonists. Drug Discovery Today 2005, 10, 693-702.
5. (a) Sorbera, L. A.; Castaner, J.; Silvestre, J. S. Rimonabant hydrochloride. Drugs Future 2005, 30, 128-137.
6. (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.
7. 1 cannabinoid receptor antagonists. J. Med. Chem. 2004, 47, 627-643.
8. 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- thioxoimidazolin-4-ones: characterization of new CB1 cannabinoid receptor inverse agonists/antagonists. J. Med. Chem. 2006, 49, 872-882;
9. (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.
10. (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 1,8-naphthyidinones and their evaluation as novel, orally active CB1 receptor inverse agonists. Bioorg. Med. Chem. Lett. 2006, 16, 681-685.
11. (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.
12. 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.
13. (b) Pines, H. S.; Chemerda, J. M.; Kozlowski, M. A.; Weinstock, L. M.; Davis, P.; Handelsman, B.; Grenda, V. J.; Lindberg, G. W. The stereochemistry of 2,3-diphenyl-1-methylpropylamine. J. Med. Chem. 1967, 10, 725-728.
14. 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.
15. 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.
16. 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.
17. 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.
18. (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.
19. (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.
20. (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.
21. (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.
22. 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 spectrometry and tritium labeling techniques. J. Mass Spectrum. 2003, 38, 211-221.
23. 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.