PF-4693627

PF-4693627 is a potent, selective and orally bioavailable microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor (IC50=3 nM) for the treatment of inflammation caused by osteoarthritis (OA) and rheumatoid arthritis (RA)[1].

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Immunology/Inflammation >> PGE synthase

IC50: 3 nM (mPGES-1)[1]

PF-4693627 also inhibits mPGES-1 with IC50s of 180 and 6 nM in HWB-1483 and human fetal fibroblast, respectively[1]. PF-4693627 shows high activity in lipopolysaccharide (LPS) stimulated human whole blood (HWB) cell assay (IC50=109 nM)[1].

PF-4693627 (10 mg/kg; orally) inhibits 63% of PGE2 production relative to vehicle control in Guinea pig carrageenan stimulated air pouch model[1]. PF-4693627 (1.0 mg/kg; i.v.) shows good bioavailability (59%) and modest half life (t1/2=3.7 h) in Sprague-Dawley rats[1]. Animal Model: Guinea pig with carrageenan stimulated air pouch inflammation model[1] Dosage: 10 mg/kg Administration: Administered orally Result: 63% PGE2 inhibition. Animal Model: Sprague-Dawley rats[1]. Dosage: 1.0 mg/kg (Pharmacokinetic Analysis) Administration: Administered i.v. Result: Clearance (CL), volume of distribution (Vdss), t1/2, mean residence time (MRT) and bioavailability (F) is 12 mL/min/kg, 3.0 L/kg, 3.7 h, 4.42 h, 59%, respectively.

[1]. Arhancet GB, et al. Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation. Bioorg Med Chem Lett. 2013 Feb 15;23(4):1114-9.