2. Academic Validation
  3. Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines

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

Affiliation

  • 1 Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri 63017, USA. grace.arhancet@gmail.com
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.

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