1. Academic Validation
  2. Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)

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

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.
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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