PF-3882845

Product NamePF-3882845
CAS1023650-66-9
MFC24H22ClN3O2
MW419.9
EINECS
MOL File1023650-66-9.mol

Chemical Properties

storage temp.	room temp
solubility	DMSO: soluble10mg/mL, clear
form	powder
color	white to beige
InChIKey	XNULRSOGWPFPBL-REWPJTCUSA-N
SMILES	OC(C1=CC2=C(C=C1)C3=NN(C4=CC=C(C#N)C(Cl)=C4)[C@@H](C5CCCC5)[C@@]3([H])CC2)=O

Safety Information

Hazard Codes	Xi
Risk Statements	36/37/38
Safety Statements	26-36/37/39
WGK Germany	3
Storage Class	11 - Combustible Solids
Hazard Classifications	Eye Irrit. 2 Skin Irrit. 2 STOT SE 3

Usage And Synthesis

Uses

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].

Biological Activity

PF-03882845 is a potent non-steroidal mineralocorticoid antagonist with and IC50 of 0.755 nM, compared to eplerenone with an IC50 of 109 nM. PF-03882845 was tested in a r at model for renal protection against aldosterone-mediated renal disease, and found to be more potent than eplerenone in suppressing the urinary albumin to creatinine ratio (UACR), a measure of renal fibrosis. The therapeutic index, calculated as the ratio of the EC50 for increasing serum K+ to the EC50 for UACR lowering, was 83.8 for PF-03882845 and 1.47 for eplerenone.

in vivo

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 (T_1/2 1.7 h) due to high plasma clearance (CL 9.8 mL/min/kg) combined with large volumes of distribution (V_dss 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.

References

[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. DOI:10.1021/jm100505n

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