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)

  • J Med Chem. 2022 Mar 10;65(5):4291-4317. doi: 10.1021/acs.jmedchem.1c02110.
Yan Shi  1 ,  Ying Wang  1 ,  Wei Meng  1 ,  Robert P Brigance  1 ,  Denis E Ryono  1 ,  Scott Bolton  1 ,  Hao Zhang  1 ,  Sean Chen  1 ,  Rebecca Smirk  1 ,  Shiwei Tao  1 ,  Joseph A Tino  2 ,  Kristin N Williams  1 ,  Richard Sulsky  1 ,  Laura Nielsen  1 ,  Bruce Ellsworth  1 ,  Michael K Y Wong  3 ,  Jung-Hui Sun  3 ,  Leslie W Leith  3 ,  Dawn Sun  3 ,  Dauh-Rurng Wu  3 ,  Anuradha Gupta  4 ,  Richard Rampulla  3 ,  Arvind Mathur  3 ,  Bang-Chi Chen  3 ,  Aiying Wang  5 ,  Helen G Fuentes-Catanio  5 ,  Lori Kunselman  5 ,  Michael Cap  5 ,  Jacob Zalaznick  5 ,  Xiaohui Ma  5 ,  Heng Liu  5 ,  Joseph R Taylor  5 ,  Rachel Zebo  5 ,  Beverly Jones  5 ,  Stephen Kalinowski  5 ,  Joann Swartz  5 ,  Ada Staal  5 ,  Kevin O'Malley  6 ,  Lisa Kopcho  6 ,  Jodi K Muckelbauer  7 ,  Stanley R Krystek Jr  7 ,  Steven A Spronk  7 ,  Jovita Marcinkeviciene  6 ,  Gerry Everlof  8 ,  Xue-Qing Chen  8 ,  Carrie Xu  8 ,  Yi-Xin Li  8 ,  Robert A Langish  8 ,  Yanou Yang  8 ,  Qi Wang  8 ,  Kamelia Behnia  8 ,  Aberra Fura  8 ,  Evan B Janovitz  9 ,  Nicola Pannacciulli  10 ,  Steven Griffen  10 ,  Bradley A Zinker  5 ,  John Krupinski  5 ,  Mark Kirby  5 ,  Jean Whaley  5 ,  Robert Zahler  1 ,  Joel C Barrish  1 ,  Jeffrey A Robl  1 ,  Peter T W Cheng  1
Affiliations
  • 1. Fibrosis Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 2. Cancer Resistance and Neuroscience Chemistry, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 3. Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 4. Department of Discovery Synthesis, Small Molecule Drug Discovery, Research & Early Development, Biocon-Bristol Myers Squibb Research & Development Center, Bangalore 560099, India.
  • 5. Cardiovascular & Fibrosis Discovery Biology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 6. Lead Evaluation, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 7. Molecular Structure & Design, Small Molecule Drug Discovery, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 8. Pharmaceutics, Preclinical Candidate Optimization, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 9. Drug Development and Preclinical Studies, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
  • 10. Clinical Pharmacology, Research & Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
PMID: 35179904 DOI: 10.1021/acs.jmedchem.1c02110
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.

Products