Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1 H -pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Autor: Shi Y; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wang Y; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Meng W; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Brigance RP; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Ryono DE; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Bolton S; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zhang H; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Chen S; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Smirk R; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Tao S; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Tino JA; Cancer Resistance and Neuroscience Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Williams KN; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Sulsky R; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Nielsen L; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Ellsworth B; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wong MKY; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Sun JH; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Leith LW; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Sun D; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wu DR; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Gupta A; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India., Rampulla R; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Mathur A; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Chen BC; Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wang A; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Fuentes-Catanio HG; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Kunselman L; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Cap M; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zalaznick J; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Ma X; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Liu H; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Taylor JR; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zebo R; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Jones B; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Kalinowski S; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Swartz J; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Staal A; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., O'Malley K; Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Kopcho L; 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Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Xu C; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Li YX; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Langish RA; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Yang Y; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Wang Q; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Behnia K; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Fura A; Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Janovitz EB; Drug Development and Preclinical Studies, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Pannacciulli N; Clinical Pharmacology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Griffen S; Clinical Pharmacology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zinker BA; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Krupinski J; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Kirby M; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Whaley J; Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Zahler R; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Barrish JC; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Robl JA; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States., Cheng PTW; Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Mar 10; Vol. 65 (5), pp. 4291-4317. Date of Electronic Publication: 2022 Feb 18.
DOI: 10.1021/acs.jmedchem.1c02110
Abstrakt: Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11 , which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.
Databáze: MEDLINE