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.

We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.

[1]  G. Steinberg,et al.  Adipose tissue as an endocrine organ , 2010, Molecular and Cellular Endocrinology.

[2]  Yue Feng,et al.  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. , 2006, Journal of medicinal chemistry.

[3]  S. McAllister,et al.  Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide oxygen/lysine3.28(192) interaction. , 2006, Journal of medicinal chemistry.

[4]  M. Maj,et al.  Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. , 2006, The Journal of clinical endocrinology and metabolism.

[5]  J. Antel,et al.  CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders. , 2006, Journal of medicinal chemistry.

[6]  G. Kennett,et al.  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 , 2006, Pharmacology Biochemistry and Behavior.

[7]  D. Scott,et al.  New bicyclic cannabinoid receptor-1 (CB1-R) antagonists. , 2006, Bioorganic & medicinal chemistry letters.

[8]  D. Cota,et al.  The emerging role of the endocannabinoid system in endocrine regulation and energy balance. , 2006, Endocrine reviews.

[9]  Arya M. Sharma,et al.  Activation of the peripheral endocannabinoid system in human obesity. , 2005, Diabetes.

[10]  T. Kirkham,et al.  Endocannabinoids in the regulation of appetite and body weight , 2005, Behavioural pharmacology.

[11]  G. Muccioli,et al.  Current knowledge on the antagonists and inverse agonists of cannabinoid receptors. , 2005, Current medicinal chemistry.

[12]  Li Di,et al.  Pharmaceutical profiling in drug discovery. , 2003, Drug discovery today.

[13]  G. Kennett,et al.  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 , 2003, Psychopharmacology.

[14]  S. Black,et al.  Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. , 2003, European journal of pharmacology.

[15]  William J Welsh,et al.  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. , 2002, Journal of medicinal chemistry.

[16]  E. Berry,et al.  Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. , 2000, European journal of pharmacology.

[17]  W. Dehaen,et al.  A Pyrazole to Furan Rearrangement. Thermolysis of 5-Azido-4-formylpyrazoles. , 1999, The Journal of organic chemistry.

[18]  P. Soubrié,et al.  SR141716A, a potent and selective antagonist of the brain cannabinoid receptor , 1994, FEBS letters.