Stereochemical requirements for the mineralocorticoid receptor antagonist activity of dihydropyridines.
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.
Arhancet
Graciela B
GB
Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri 63017, USA. grace.arhancet@gmail.com
Woodard
Scott S
SS
Dietz
Jessica D
JD
Garland
Danny J
DJ
Wagner
Grace M
GM
Iyanar
Kaliappan
K
Collins
Joe T
JT
Blinn
James R
JR
Numann
Randal E
RE
Hu
Xiao
X
Huang
Horng-Chih
HC
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
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D008156:Luciferases