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

  • J Med Chem. 2015 Sep 24;58(18):7173-85. doi: 10.1021/acs.jmedchem.5b01006.
Kentaro Futatsugi  1  2 ,  Daniel W Kung  1  2 ,  Suvi T M Orr  1  2 ,  Shawn Cabral  1  2 ,  David Hepworth  1  2 ,  Gary Aspnes  1  2 ,  Scott Bader  1  2 ,  Jianwei Bian  1  2 ,  Markus Boehm  1  2 ,  Philip A Carpino  1  2 ,  Steven B Coffey  1  2 ,  Matthew S Dowling  1  2 ,  Michael Herr  1  2 ,  Wenhua Jiao  1  2 ,  Sophie Y Lavergne  1  2 ,  Qifang Li  1  2 ,  Ronald W Clark  1  2 ,  Derek M Erion  1  2 ,  Kou Kou  1  2 ,  Kyuha Lee  1  2 ,  Brandon A Pabst  1  2 ,  Sylvie M Perez  1  2 ,  Julie Purkal  1  2 ,  Csilla C Jorgensen  1  2 ,  Theunis C Goosen  1  2 ,  James R Gosset  1  2 ,  Mark Niosi  1  2 ,  John C Pettersen  1  2 ,  Jeffrey A Pfefferkorn  1  2 ,  Kay Ahn  1  2 ,  Bryan Goodwin  1  2
Affiliations
  • 1. Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.
  • 2. Worldwide Medicinal Chemistry, ⊥Cardiovascular, Metabolic and Endocrine Diseases Research Unit, #Pharmacokinetics, Dynamics and Metabolism, ∇Pharmaceutical Sciences, and ○Drug Safety Research & Development, Pfizer Worldwide Research & Development , Groton, Connecticut 06340, United States.
PMID: 26349027 DOI: 10.1021/acs.jmedchem.5b01006
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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