PF-3882845

PF-3882845 is a remarkably high affinity selective and orally efficacious mineralocorticoid receptor (MR binding IC50=2.7 nM) antagonist for hypertension and nephropathy. PF-3882845 also binds to progesterone receptor (PR) with the binding IC50 of 310 nM[1].

Signaling Pathways >> Others >> Progesterone Receptor

Research Areas >> Cardiovascular Disease

Signaling Pathways >> Metabolic Enzyme/Protease >> Mineralocorticoid Receptor

Research Areas >> Metabolic Disease

IC50: 2.7 nM (mineralocorticoid receptor), 310 nM (progesterone receptor)[1]

PF-3882845 reduces blood pressure, decreases urinary albumin, and protects kidney in Dahl SS rat[1]. PF-3882845 exhibits moderate oral bioavailability (F 86%) following oral administration (2 mg/kg) in male Sprague-Dawley rats[1]. PF-3882845 exhibits terminal elimination half-lives (T1/2 1.7 h) due to high plasma clearance (CL 9.8 mL/min/kg) combined with large volumes of distribution (Vdss 1.4 mL/kg respectively) following intravenous administration (2 mg/kg) in male Sprague-Dawley rats[1]. Animal Model: Male Dahl salt sensitive (SS) rats[1] Dosage: 10, 40, and 100 mg/kg Administration: Orally via gavage; twice a day; for 21 days Result: Significant blood pressure reduction was observed with 10 mg/kg. Most noticeably, rats dosed at 40 and 100 mg/kg had negligible increase in blood pressure over 21 days in the presence of high salt.

[1]. Meyers MJ, et al. 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. J Med Chem. 2010 Aug 26;53(16):5979-6002.