Discovery of Novel Cyanodihydropyridines as Potent Mineralocorticoid Receptor Antagonists
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- 作者：Graciela B. Arhancet ; Scott S. Woodard ; Kaliappan Iyanar ; Brenda L. Case ; Rhonda Woerndle ; Jessica D. Dietz ; Danny J. Garland ; Joe T. Collins ; Maria A. Payne ; James R. Blinn ; Silvia I. Pomposiello ; Xi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 26, 2010
- 年：2010
- 卷：53
- 期：16
- 页码：5970-5978
- 全文大小：928K
- 年卷期：v.53,no.16(August 26, 2010)
- ISSN：1520-4804
文摘
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.