학술논문
Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)methyl)phosphonate (BMS-820132)
Document Type
Article
Author
Shi, Yan; Wang, Ying; Meng, Wei; Brigance, Robert P.; Ryono, Denis E.; Bolton, Scott; Zhang, Hao; Chen, Sean; Smirk, Rebecca; Tao, Shiwei; Tino, Joseph A.; Williams, Kristin N.; Sulsky, Richard; Nielsen, Laura; Ellsworth, Bruce; Wong, Michael K. Y.; Sun, Jung-Hui; Leith, Leslie W.; Sun, Dawn; Wu, Dauh-Rurng; Gupta, Anuradha; Rampulla, Richard; Mathur, Arvind; Chen, Bang-Chi; Wang, Aiying; Fuentes-Catanio, Helen G.; Kunselman, Lori; Cap, Michael; Zalaznick, Jacob; Ma, Xiaohui; Liu, Heng; Taylor, Joseph R.; Zebo, Rachel; Jones, Beverly; Kalinowski, Stephen; Swartz, Joann; Staal, Ada; O’Malley, Kevin; Kopcho, Lisa; Muckelbauer, Jodi K.; Krystek, Stanley R.; Spronk, Steven A.; Marcinkeviciene, Jovita; Everlof, Gerry; Chen, Xue-Qing; Xu, Carrie; Li, Yi-Xin; Langish, Robert A.; Yang, Yanou; Wang, Qi; Behnia, Kamelia; Fura, Aberra; Janovitz, Evan B.; Pannacciulli, Nicola; Griffen, Steven; Zinker, Bradley A.; Krupinski, John; Kirby, Mark; Whaley, Jean; Zahler, Robert; Barrish, Joel C.; Robl, Jeffrey A.; Cheng, Peter T. W.
Source
Journal of Medicinal Chemistry; March 2022, Vol. 65 Issue: 5 p4291-4317, 27p
Subject
Language
ISSN
00222623; 15204804
Abstract
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 vitroand in vivopreclinical pharmacology profiles of 31and its pharmacokinetics (PK) are described. Based on its promising in vivoefficacy and preclinical ADME and safety profiles, 31was advanced into human clinical trials.