Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

Journal of Medicinal Chemistry
Kentaro FutatsugiBryan Goodwin

Abstract

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

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Citations

Nov 13, 2015·Journal of Medicinal Chemistry·Jason E ImbriglioAndrew Taggart
Aug 11, 2015·Journal of Medicinal Chemistry·Kim HuardKay Ahn
Apr 26, 2016·The Journal of Organic Chemistry·Jessy AzizSandrine Piguel
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