Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

  • J Med Chem. 2024 Jun 13;67(11):9731-9744. doi: 10.1021/acs.jmedchem.4c00893.
Jeremy M Richter  1 ,  Prashantha Gunaga  2 ,  Navnath Yadav  2 ,  Rajesh Onkardas Bora  2 ,  Rajeev Bhide  1 ,  Nagendra Rajugowda  2 ,  Kavitha Govindrajulu  2 ,  Sreenivasulu Godesi  2 ,  Nagarjuna Akuthota  2 ,  Prasanna Rao  2 ,  Aneesh Sivaraman  2 ,  Manoranjan Panda  1 ,  Mahammed Kaspady  2 ,  Anuradha Gupta  1 ,  Arvind Mathur  1 ,  Paul C Levesque  1 ,  Jyoti Gulia  2 ,  Manoj Dokania  2 ,  Manjunath Ramarao  1 ,  Prashant Kole  2 ,  Silvi Chacko  1 ,  Kimberley A Lentz  1 ,  Sankara Sivaprasad Lvj  2 ,  Rajendra Prasad Thatipamula  2 ,  Srikanth Sridhar  2 ,  Shyam Kamble  2 ,  Arun Govindrajan  2 ,  Sharif I Soleman  1 ,  David A Gordon  1 ,  Ruth R Wexler  1 ,  E Scott Priestley  1
Affiliations
  • 1. Bristol Myers Squibb Research & Early Development, Princeton, New Jersey 08540, United States.
  • 2. Biocon Bristol Myers Squibb Research Center, Syngene International Limited, Bangalore 560099, India.
PMID: 38807539 DOI: 10.1021/acs.jmedchem.4c00893
Abstract

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

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