2. Academic Validation
  3. 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.
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.

Figures
Products