title: Discovery and optimization of 2-phenyloxazole derivatives as diacylglycerol acyltransferase-1 inhibitors.
abstract: In a discovery effort to find safe and effective DGAT-1 inhibitors, we have identified 2-phenyloxazole 4-carboxamide 1 as a conformationally constrained analog of a hydrazide hit, which was previously identified from high-throughput screening. Further optimization of this series has led to chemically more stable 2-phenyloxazole-based DGAT-1 inhibitor 25 with improved solubility, cell-based activity, and pharmacokinetic properties. Compound 25 also demonstrated in vivo efficacy in a diet-induced obesity (DIO) rat model.
authors: Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. weiya.yun@roche.com
authors: Weiya
authors: W
authors: Yun
authors: Mushtaq
authors: M
authors: Ahmad
authors: Yingsi
authors: Y
authors: Chen
authors: Paul
authors: P
authors: Gillespie
authors: Karin
authors: K
authors: Conde-Knape
authors: Sonja
authors: S
authors: Kazmer
authors: Shiming
authors: S
authors: Li
authors: Yimin
authors: Y
authors: Qian
authors: Rebecca
authors: R
authors: Taub
authors: Stanley J
authors: SJ
authors: Wertheimer
authors: Toni
authors: T
authors: Whittard
authors: David
authors: D
authors: Bolin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004195:Disease Models, Animal; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010080:Oxazoles; D051048:Diacylglycerol O-Acyltransferase