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

Autor: Futatsugi K; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Kung DW; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Orr ST; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Cabral S; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Hepworth D; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Aspnes G; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Bader S; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Bian J; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Boehm M; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Carpino PA; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Coffey SB; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Dowling MS; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Herr M; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Jiao W; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Lavergne SY; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Li Q; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Clark RW; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Erion DM; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Kou K; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Lee K; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Pabst BA; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Perez SM; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Purkal J; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Jorgensen CC; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Goosen TC; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Gosset JR; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Niosi M; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Pettersen JC; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Pfefferkorn JA; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Ahn K; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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., Goodwin B; Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and §Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development , Cambridge, Massachusetts 02139, United States.; 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.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2015 Sep 24; Vol. 58 (18), pp. 7173-85.
DOI: 10.1021/acs.jmedchem.5b01006
Abstrakt: 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.
Databáze: MEDLINE