Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines

  • J Med Chem. 2010 May 27;53(10):4300-4. doi: 10.1021/jm1002827.
Graciela B Arhancet  1 ,  Scott S Woodard ,  Jessica D Dietz ,  Danny J Garland ,  Grace M Wagner ,  Kaliappan Iyanar ,  Joe T Collins ,  James R Blinn ,  Randal E Numann ,  Xiao Hu ,  Horng-Chih Huang
Affiliations
  • 1. Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri 63017, USA. [email protected]
PMID: 20408553 DOI: 10.1021/jm1002827
Abstract

A number of known 1,4-dihydropyridine CCBs were identified as having comparable potency to the steroidal MR antagonist eplerenone. Chiral resolution of mebudipine revealed that MR and CCB activity reside in opposite enantiomers. Small molecule X-ray crystal structures showed that the C4 stereochemistry of optimized selective MR analogues, e.g. 5, is consistent with MR-active mebudipine. Molecular modeling supports a binding pose consistent with that previously proposed for DHP diesters.