title: Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines.
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.
authors.affiliation: Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri 63017, USA. grace.arhancet@gmail.com
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Arhancet
authors.forename: Scott S
authors.initials: SS
authors.lastname: Woodard
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Dietz
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Garland
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wagner
authors.forename: Kaliappan
authors.initials: K
authors.lastname: Iyanar
authors.forename: Joe T
authors.initials: JT
authors.lastname: Collins
authors.forename: James R
authors.initials: JR
authors.lastname: Blinn
authors.forename: Randal E
authors.initials: RE
authors.lastname: Numann
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology; D000077545:Eplerenone; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D000451:Mineralocorticoid Receptor Antagonists; D008958:Models, Molecular; D011485:Protein Binding; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D008156:Luciferases