title: Discovery of orally active carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamide as potent diacylglycerol acyltransferase-1 inhibitors for the potential treatment of obesity and diabetes.
abstract: Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).
authors.affiliation: Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States. yimin.qian@roche.com
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wertheimer
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmad
authors.forename: Adrian Wai-Hing
authors.initials: AW
authors.lastname: Cheung
authors.forename: Fariborz
authors.initials: F
authors.lastname: Firooznia
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hamilton
authors.forename: Stuart
authors.initials: S
authors.lastname: Hayden
authors.forename: Shiming
authors.initials: S
authors.lastname: Li
authors.forename: Nicholas
authors.initials: N
authors.lastname: Marcopulos
authors.forename: Lee
authors.initials: L
authors.lastname: McDermott
authors.forename: Jenny
authors.initials: J
authors.lastname: Tan
authors.forename: Weiya
authors.initials: W
authors.lastname: Yun
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Anjula
authors.initials: A
authors.lastname: Pamidimukkala
authors.forename: Yingsi
authors.initials: Y
authors.lastname: Chen
authors.forename: Kuo-Sen
authors.initials: KS
authors.lastname: Huang
authors.forename: Gwendolyn B
authors.initials: GB
authors.lastname: Ramsey
authors.forename: Toni
authors.initials: T
authors.lastname: Whittard
authors.forename: Karin
authors.initials: K
authors.lastname: Conde-Knape
authors.forename: Rebecca
authors.initials: R
authors.lastname: Taub
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Rondinone
authors.forename: Jefferson
authors.initials: J
authors.lastname: Tilley
authors.forename: David
authors.initials: D
authors.lastname: Bolin
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry*; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004285:Dogs; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D010080:Oxazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D000577:Amides; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D010080:Oxazoles; D051048:Diacylglycerol O-Acyltransferase