Discovery of Tetralones as Potent and Selective Inhibitors of Acyl-CoA:Diacylglycerol Acyltransferase 1

• Published in: ACS medicinal chemistry letters Vol. 9; no. 2; pp. 103 - 108
• Main Authors: Cheung, Mui, Tangirala, Raghuram S, Bethi, Sridhar R, Joshi, Hemant V, Ariazi, Jennifer L, Tirunagaru, Vijaya G, Kumar, Sanjay
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08-02-2018
• Subjects: Letter; genotoxicity; metabolic disorders; mutagenicity; Ames; tetralones; DGAT1 inhibitors; GSK2973980A; aniline; acyltransferase
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.7b00450

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) plays an important role in triglyceride synthesis and is a target of interest for the treatment of metabolic disorders. Herein we describe the structure–activity relationship of a novel tetralone series of DGAT1 inhibitors and our strategies for overcoming genotoxic liability of the anilines embedded in the chemical structures, leading to the discovery of a candidate compound, (S)-2-(6-(5-(3-(3,4-difluorophenyl)­ureido)­pyrazin-2-yl)-1-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)­acetic acid (GSK2973980A, 26d). Compound 26d is a potent and selective DGAT1 inhibitor with excellent DMPK profiles and in vivo efficacy in a postprandial lipid excursion model in mice. Based on the overall biological and developability profiles and acceptable safety profiles in the 7-day toxicity studies in rats and dogs, compound 26d was selected as a candidate compound for further development in the treatment of metabolic disorders.