Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1<i>H</i>-pyrazol-1-yl)methyl)phosphonate (BMS-820132)
Yan Shi, Wang Ying, Wei Meng, Robert Brigance, Denis E. Ryono, Scott A. Bolton, Hao Zhang, Sean Chen, Rebecca A. Smirk, Shiwei Tao, Joseph A. Tino, Kristin N. Williams, Richard Sulsky, Laura Nielsen, Bruce A. Ellsworth, Michael K. Y. Wong, Jung‐Hui Sun, Leslie Leith, Dawn Sun, Dauh‐Rurng Wu, Anuradha Gupta, Richard Rampulla, Arvind Mathur, Bang‐Chi Chen, Aiying Wang, Helen G. Fuentes-Catanio, Lori Kunselman, Michael Cap, Jacob Zalaznick, Xiaohui Ma, Heng Liu, Joseph R. Taylor, Rachel Zebo, Beverly Jones, Stephen Kalinowski, Joann Swartz, Ada Staal, K O'Malley, Lisa M. Kopcho, J.K. Muckelbauer, Stanley R. Krystek, Steven A. Spronk, Jovita Marcinkeviciene, Gerry Everlof, Xueqing Chen, Carrie Xu, Yixin Li, Robert A. Langish, Yanou Yang, Qi Wang, Kamelia Behnia, Aberra Fura, Evan B. Janovitz, Nicola Pannacciulli, Steven C. Griffen, Bradley A. Zinker, John Krupinski, Mark Kirby, Jean M. Whaley, Robert Zahler, Joel C. Barrish, Jeffrey A. Robl, Peter T. W. Cheng
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 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.