title: Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.
abstract: 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.
authors.affiliation: St. Louis Laboratories, Pfizer Global Research and Development, Pfizer, Inc., 700 Chesterfield Parkway West, St. Louis, Missouri 63017, USA. graciela.arhancet@novusint.com
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Arhancet
authors.forename: Scott S
authors.initials: SS
authors.lastname: Woodard
authors.forename: Kaliappan
authors.initials: K
authors.lastname: Iyanar
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Case
authors.forename: Rhonda
authors.initials: R
authors.lastname: Woerndle
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Dietz
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Garland
authors.forename: Joe T
authors.initials: JT
authors.lastname: Collins
authors.forename: Maria A
authors.initials: MA
authors.lastname: Payne
authors.forename: James R
authors.initials: JR
authors.lastname: Blinn
authors.forename: Silvia I
authors.initials: SI
authors.lastname: Pomposiello
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Heron
authors.forename: Horng-Chih
authors.initials: HC
authors.lastname: Huang
authors.forename: Len F
authors.initials: LF
authors.lastname: Lee
mesh_terms: 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
chemical_list: D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D009570:Nitriles; D011725:Pyridines