Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.

Abstract	We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.
Authors	Marvin J Meyers, Graciela B Arhancet, Susan L Hockerman, Xiangyang Chen, Scott A Long, Matthew W Mahoney, Joseph R Rico, Danny J Garland, James R Blinn, Joe T Collins, Shengtian Yang, Horng-Chih Huang, Kevin F McGee, Jay M Wendling, Jessica D Dietz, Maria A Payne, Bruce L Homer, Marcia I Heron, David B Reitz, Xiao Hu
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 16 Pg. 5979-6002 (Aug 26 2010) ISSN: 1520-4804 [Electronic] United States
PMID	20672822 (Publication Type: Journal Article)
Chemical References	Antihypertensive Agents Chlorobenzenes Indazoles Indenes Mineralocorticoid Receptor Antagonists Nitriles (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo(g)indazole-7-carboxylic acid
Topics	Animals Antihypertensive Agents (chemical synthesis, pharmacokinetics, pharmacology) Blood Pressure (drug effects) Cell Line, Tumor Chlorobenzenes Crystallography, X-Ray Humans Hypertension (drug therapy) Indazoles (chemical synthesis, pharmacokinetics, pharmacology) Indenes Kidney Diseases (drug therapy) Male Mineralocorticoid Receptor Antagonists Models, Molecular Molecular Conformation Nitriles (chemical synthesis, pharmacokinetics, pharmacology) Radioligand Assay Rats Rats, Inbred Dahl Rats, Sprague-Dawley Stereoisomerism Structure-Activity Relationship

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