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

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.

SUBMITTER: Yang C

PROVIDER: S-EPMC4416436 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Yang Christine C Balsells Jaume J Chu Hong D HD Cox Jason M JM Crespo Alejandro A Ma Xiuying X Contino Lisa L Brown Patricia P Gao Sheng S Zamlynny Beata B Wiltsie Judyann J Clemas Joseph J Lisnock JeanMarie J Gibson Jack J Zhou Gaochao G Garcia-Calvo Margarita M Bateman Thomas J TJ Tong Vincent V Xu Ling L Crook Martin M Sinclair Peter P Shen Hong C HC

ACS medicinal chemistry letters 20150306 4

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 natriures ...[more]

PMID: 25941555

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