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

Kentaro Futatsugi, Daniel W Kung, Suvi T M Orr, Shawn Cabral, David Hepworth, Gary Aspnes, Scott Bader, Jianwei Bian, Markus Boehm, Philip A Carpino, Steven B Coffey, Matthew S Dowling, Michael Herr, Wenhua Jiao, etc.

J Med Chem. 2015 Sep 24;58(18):7173-85.

PMID: 26349027

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
AP1469284794 PF-06424439 PF-06424439 1469284-79-4 Price
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