Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.

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Arhancet GB, Woodard SS, Iyanar K, Case BL, Woerndle R, Dietz JD, Garland DJ, Collins JT, Payne MA, Blinn JR, Pomposiello SI, Hu X, Heron MI, Huang HC, Lee LF

Discovery of novel cyanodihydropyridines as potent mineralocorticoid receptor antagonists.

J Med Chem. 2010 Aug 26;53(16):5970-8. doi: 10.1021/jm100506y.

PubMed ID

20672820 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Eplerenone	Mineralocorticoid receptor	IC 50 (nM)	122	N/A	N/A	Details