Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)- 6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8-(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity

Journal of Medicinal Chemistry

Volumn 52, Issue 9, 2009, Pages 2652-2655

  Dow, Robert L ^a   Carpino, Philip A ^a   Hadcock, John R ^a   Black, Shawn C ^a,b   Iredale, Philip A ^a   DaSilva Jardine, Paul ^a   Schneider, Steven R ^a   Paight, Ernest S ^a   Griffith, David A ^a   Scott, Dennis O ^a   O'Connor, Rebecca E ^a   Nduaka, Chudy I ^a  

^a PFIZER INC   (United States)

^b JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; CANNABINOID 1 RECEPTOR; CANNABINOID 1 RECEPTOR ANTAGONIST; PF 514273; RIMONABANT; TARANABANT;

ANALGESIA; ANIMAL BEHAVIOR; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CATALEPSY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; FOOD INTAKE; HYPOTHERMIA; LOCOMOTION; NONHUMAN; OBESITY; RAT; REACTION ANALYSIS;

ANIMALS; CLINICAL TRIALS AS TOPIC; CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; HUMANS; LACTAMS; OBESITY; OXAZEPINES; PYRAZOLES; RATS; RECEPTOR, CANNABINOID, CB1;

EID: 65649104424     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900255t     Document Type: Article

References (23)

1. Kershaw, E. E.; Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 2004, 89, 2548-2556. (Pubitemid 38766330)
2. Kirkham, T. C. Endocannabinoids in the regulation of appetite and body weight. Behav. Pharmacol. 2005, 16, 297-313. (Pubitemid 41404803)
3. Pagotto, U.; Marsicano, G.; Cota, D.; Lutz, B.; Pasquali, R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. 2006, 27, 73-100. (Pubitemid 43228239)
4. Matias, I.; Gonthier, M. P.; Orlando, P.; Martiadis, V.; De Petrocellis, L.; Cervino, C.; Petrosino, S.; Hoareau, L.; Festy, F.; Pasquali, R.; Roche, R.; Maj, M.; Pagotto, U.; Monteleone, P.; Di Marzo, V. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 2006, 91, 3171-3180. (Pubitemid 44271774)
5. Hao, S.; Avraham, Y.; Mechoulam, R.; Berry, E. M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur. J. Pharmacol. 2000, 392, 147-156. (Pubitemid 30184903)
6. Engeli, S.; Böhnke, J.; Feldpausch, M.; Gorzelniak, K.; Janke, J.; Bátkai, S.; Pacher, P.; Harvey-White, J.; Luft, F. C.; Sharma, A. M.; Jordan, J. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005, 54, 2838-2843. (Pubitemid 41401077)
7. Kirkham, T. C.; Williams, C. M.; Fezza, F.; Di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol. 2002, 136, 550-557. (Pubitemid 34717699)
8. Jbilo, O.; Ravinet-Trillou, C.; Arnone, M.; Buisson, I.; Bribes, E.; Péleraux, A.; Pénarier, G.; Soubrié, P.; Le Fur, G.; Galiègue, S.; Casellas, P. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005, 19, 1567-1569. (Pubitemid 41279033)
9. Thornton-Jones, Z. D.; Kennett, G. A.; Benwell, K. R.; Revell, D. F.; Misra, A.; Sellwood, D. M.; Vickers, S. P.; Clifton, P. G. The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake. Pharmacol., Biochem. Behav. 2006, 84, 353-359. (Pubitemid 44137303)
10. Vickers, S. P.; Webster, L. J.; Wyatt, A.; Dourish, C. T.; Kennett, G. A. Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology (Berlin, Ger.) 2003, 167, 103-111. (Pubitemid 36535298)
11. Hildebrandt, A. L.; Kelly-Sullivan, D. M.; Black, S. C. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur. J. Pharmacol. 2003, 462, 125-132. (Pubitemid 36183743)
12. Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Néliat, G.; Caput, D.; et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994, 350, 240-244.
13. Lin, L. S.; Lanza, T. J., Jr.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.; Xu, S. S.; Fong, T. M.; Shen, C. P.; Lao, J.; Xiao, J. C.; Shearman, L. P.; Stribling, D. S.; Rosko, K.; Strack, A.; Marsh, D. J.; Feng, Y.; Kumar, S.; Samuel, K.; Yin, W.; Van der Ploeg, L. H.; Goulet, M. T.; Hagmann, W. K. 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. J. Med. Chem. 2006, 49, 7584-7587. (Pubitemid 46033647)
14. 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.; Lizano, 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. (Pubitemid 43014870)
15. Lipinski, C. A. In Pharmaceutical Profiling in Drug Discovery for Lead Selection; Borchardt, R. T., Kerns, E. H., Lipinski, C. A., Thakker, D. R., Wang, B., Eds.; AAPS Press: Arlington, VA, 2004; Part II, Chapter 1, pp 93-126.
16. Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman, A. F.; Mukhin, A. G.; Horti, A. G. Synthesis, structure-activity relationship, and evaluation of SR141716 analogues: development of central cannabinoid receptor ligands with lower lipophilicity. J. Med. Chem. 2003, 46, 642-645. (Pubitemid 36182766)
17. Svenstrup, N.; Simonsen, K. B.; Thorup, N.; Brodersen, J.; Dehaen, W.; Becher, J. A pyrazole to furan rearrangement. Thermolysis of 5-azido-4-formylpyrazoles. J. Org. Chem. 1999, 64, 2814-2820. (Pubitemid 129511032)
18. Soliman, F. S. G.; Shafik, R. M. Polysubstituted pyrazoles. Pharmazie 1975, 30, 436-439.
19. (a) Muccioli, G. G.; Lambert, D. M. Current knowledge on the antagonists and inverse agonists of cannabinoid receptors. Curr. Med. Chem. 2005, 12, 1361-1394. (Pubitemid 40872582)
20. (b) Antel, J.; Gregory, P. C.; Nordheim, U. CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders. J. Med. Chem. 2006, 49, 4008-4016. (Pubitemid 44036646)
21. At exposures of ≥10x the efficacious plasma concentrations in Sprague-Dawley rats, 3 exhibited substantial clinical signs (decreased acitivity and rapid respiration). Similar narrow therapeutic indexes were observed for other members of this chemical class. These side effects and their associated TI were chemical class dependent, suggesting it is not mechanism related.
22. (a) Shim, J.-Y.; Welsh, W. J.; Cartier, E.; Edwards, J. L.; Howlett, A. C. Molecular interaction of the antagonist N-(piperidin-1-yl)-5-4-(chlorophenyl) -1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor. J. Med. Chem. 2002, 45, 1447-1459. (Pubitemid 34246108)
23. (b) Hurst, D.; Umejiego, U.; Lynch, D.; Seltzman, H.; Hyatt, S.; Roche, M.; McAllister, S.; Fleischer, D.; Kapur, A.; Abood, M.; Shi, S.; Jones, J.; Lewis, D.; Reggio, P. Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. J. Med. Chem. 2006, 49, 5969-5987. (Pubitemid 44484943)