Journal of Medicinal Chemistry · 2010 · 38 citations · 0 references
PharmacyMedicinal ChemistryPharmacologyDrug DiscoveryMolecular PharmacologyStructure-activity RelationshipsChiral RecognitionDrug-receptor InteractionsLigand BindingPotency OptimizationReceptor PharmacologyStereochemical OptimizationChiral SelectionMineralocorticoid ActivityMineralocorticoid Receptor PharmacologyStereochemical DescriptorsStereochemical MechanismsStereochemical RequirementsStereochemical Structure - Activity RelationshipStereochemical Structure-activity Relationships
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.