Discovery of Novel Cyanodihydropyridines as Potent Mineralocorticoid Receptor Antagonists

作者：Arhancet Graciela B^*; Woodard Scott S; Iyanar Kaliappan; Case Brenda L; Woerndle Rhonda; Dietz Jessica D; Garland Danny J; Collins Joe T; Payne Maria A; Blinn James R; Pomposiello Silvia I; Hu Xiao; Heron Marcia I; Huang Horng Chih; Lee Len F

来源：Journal of Medicinal Chemistry, 2010, 53(16): 5970-5978.

DOI：10.1021/jm100506y

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 R(6) 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 R(6) 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.

• 出版日期2010-8-26