Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.
A new 1,4-dihydropyridine 5a, containing a cyano group at the C3 position, was recently reported to possess excellent mineralocorticoid receptor (MR) antagonist in vitro potency and no calcium channel-blocker (CCB) activity. In the present study, we report the structure-activity relationships of this novel series of cyano ester dihydropyridines that resulted in R6 substituted analogues with improved metabolic stability while maintaining excellent MR antagonist activity and selectivity against other nuclear receptors. Further structure optimization with the introduction of five-membered ring heterocycles at R6 resulted in compounds with excellent MR antagonist potency and a suitable pharmacokinetic profile. In vivo studies of a promising tool compound in the Dahl salt-sensitive rat model of hypertension showed similar blood pressure (BP) reduction as the steroidal MR antagonist eplerenone, providing proof-of-concept (POC) for a nonsteroidal, orally efficacious MR antagonist.
Arhancet
Graciela B
GB
St. Louis Laboratories, Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West, St. Louis, Missouri 63017, USA. graciela.arhancet@novusint.com
Woodard
Scott S
SS
Iyanar
Kaliappan
K
Case
Brenda L
BL
Woerndle
Rhonda
R
Dietz
Jessica D
JD
Garland
Danny J
DJ
Collins
Joe T
JT
Payne
Maria A
MA
Blinn
James R
JR
Pomposiello
Silvia I
SI
Hu
Xiao
X
Heron
Marcia I
MI
Huang
Horng-Chih
HC
Lee
Len F
LF
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D009570:Nitriles; D011725:Pyridines