| Literature DB >> 26349027 |
Kentaro Futatsugi1,2, Daniel W Kung1,2, Suvi T M Orr1,2, Shawn Cabral1,2, David Hepworth1,2, Gary Aspnes1,2, Scott Bader1,2, Jianwei Bian1,2, Markus Boehm1,2, Philip A Carpino1,2, Steven B Coffey1,2, Matthew S Dowling1,2, Michael Herr1,2, Wenhua Jiao1,2, Sophie Y Lavergne1,2, Qifang Li1,2, Ronald W Clark1,2, Derek M Erion1,2, Kou Kou1,2, Kyuha Lee1,2, Brandon A Pabst1,2, Sylvie M Perez1,2, Julie Purkal1,2, Csilla C Jorgensen1,2, Theunis C Goosen1,2, James R Gosset1,2, Mark Niosi1,2, John C Pettersen1,2, Jeffrey A Pfefferkorn1,2, Kay Ahn1,2, Bryan Goodwin1,2.
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.Entities:
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Year: 2015 PMID： 26349027 DOI： 10.1021/acs.jmedchem.5b01006
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446