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

Mui Cheung; Raghuram S Tangirala; Sridhar R Bethi; Hemant V Joshi; Jennifer L Ariazi; Vijaya G Tirunagaru; Sanjay Kumar

doi:10.1021/acsmedchemlett.7b00450

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

ACS Med Chem Lett. 2018 Jan 16;9(2):103-108. doi: 10.1021/acsmedchemlett.7b00450. eCollection 2018 Feb 8.

Authors

Mui Cheung¹, Raghuram S Tangirala², Sridhar R Bethi², Hemant V Joshi², Jennifer L Ariazi¹, Vijaya G Tirunagaru², Sanjay Kumar¹

Affiliations

¹ Virtual Proof of Concept Discovery Performance Unit, Alternative Discovery and Development, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
² Collaborative Research, GVK Biosciences Private Limited, 28A, IDA, Nacharam, Hyderabad 500076, India.

Abstract

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.