Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors.

Autor: Imbriglio JE; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Shen DM; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Liang R; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Marby K; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., You M; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Youm HW; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Feng Z; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., London C; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Xiong Y; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Tata J; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Verras A; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Garcia-Calvo M; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Song X; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Addona GH; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., McLaren DG; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., He T; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Murphy B; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Metzger DE; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Salituro G; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Deckman D; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Chen Q; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Jin X; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Stout SJ; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Wang SP; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Wilsie L; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Palyha O; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Han S; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Hubbard BK; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Previs SF; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Pinto S; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States., Taggart A; Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2015 Dec 10; Vol. 58 (23), pp. 9345-53. Date of Electronic Publication: 2015 Nov 20.
DOI: 10.1021/acs.jmedchem.5b01345
Abstrakt: DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
Databáze: MEDLINE