pf-03882845 and Hypertension

pf-03882845 has been researched along with Hypertension* in 1 studies

Other Studies

1 other study(ies) available for pf-03882845 and Hypertension

Article	Year
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. Journal of medicinal chemistry, 2010, Aug-26, Volume: 53, Issue:16 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. Topics: Animals; Antihypertensive Agents; Blood Pressure; Cell Line, Tumor; Chlorobenzenes; Crystallography, X-Ray; Humans; Hypertension; Indazoles; Indenes; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Models, Molecular; Molecular Conformation; Nitriles; Radioligand Assay; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship	2010

Article

Year

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.

Journal of medicinal chemistry, 2010, Aug-26, Volume: 53, Issue:16

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.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cell Line, Tumor; Chlorobenzenes; Crystallography, X-Ray; Humans; Hypertension; Indazoles; Indenes; Kidney Diseases; Male; Mineralocorticoid Receptor Antagonists; Models, Molecular; Molecular Conformation; Nitriles; Radioligand Assay; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship

2010