2. Academic Validation
  3. Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists

Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists

  • ACS Med Chem Lett. 2015 Mar 6;6(4):461-5. doi: 10.1021/acsmedchemlett.5b00010.
Christine Yang 1,  Jaume Balsells 1,  Hong D Chu 1,  Jason M Cox 1,  Alejandro Crespo 1,  Xiuying Ma 1,  Lisa Contino 1,  Patricia Brown 1,  Sheng Gao 1,  Beata Zamlynny 1,  Judyann Wiltsie 1,  Joseph Clemas 1,  JeanMarie Lisnock 1,  Jack Gibson 1,  Gaochao Zhou 1,  Margarita Garcia-Calvo 1,  Thomas J Bateman 1,  Vincent Tong 1,  Ling Xu 1,  Martin Crook 1,  Peter Sinclair 1,  Hong C Shen 1
Affiliations

Affiliation

  • 1 Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
PMID: 25941555 DOI: 10.1021/acsmedchemlett.5b00010
Abstract

Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal Mineralocorticoid Receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.

Keywords

amide replacement; antagonist; mineralocorticoid receptor; natriuresis effect; oxazolidinedione.

Figures