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; Sophie Y Lavergne; Qifang Li; Ronald W Clark; Derek M Erion; Kou Kou; Kyuha Lee; Brandon A Pabst; Sylvie M Perez; Julie Purkal; Csilla C Jorgensen; Theunis C Goosen; James R Gosset; Mark Niosi; John C Pettersen; Jeffrey A Pfefferkorn; Kay Ahn; Bryan Goodwin

doi:10.1021/acs.jmedchem.5b01006

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.

Authors

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.

MeSH terms

Animals
Cyclopropanes / chemistry
Cyclopropanes / pharmacokinetics
Cyclopropanes / pharmacology
Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
Dogs
Dyslipidemias / drug therapy
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Imidazoles / chemistry*
Imidazoles / pharmacokinetics
Imidazoles / pharmacology
Lipid Metabolism / drug effects
Male
Mice, Knockout
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology
Pyrrolidines / chemistry*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology
Rats
Rats, Sprague-Dawley
Receptors, LDL / genetics
Sf9 Cells
Spodoptera
Stereoisomerism
Structure-Activity Relationship

Substances

Cyclopropanes
Imidazoles
PF-06424439
Pyridines
Pyrrolidines
Receptors, LDL
Diacylglycerol O-Acyltransferase