Encequidar

Encequidar is a potent and selective P-glycoprotein inhibitor. HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC (50), tariquidar: 8.2 2.0 nM, HM30181: 13.1 2.3 nM) . PET scans with the Pgp substrate (R) -[ (11) C]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in (R) -[ (11) C]verapamil brain uptake compared with vehicle treated animals. PET scans with [ (11) C]HM30181 showed low and not significantly different brain uptake of [ (11) C]HM30181 in wild-type, Mdr1a/b ((-/-) ) and Bcrp1 ((-/-) ) mice and significantly, i.e. 4.7-fold (P<0.01), higher brain uptake, relative to wild-type animals, in Mdr1a/b ((-/-) ) Bcrp1 ((-/-) ) mice. (In Vitro) :Encequidar (HM30181; HM30181A) is shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC50, tariquidar: 8.2±2.0 nM, Encequidar (HM30181) : 13.1±2.3 nM) .Encequidar (HM30181) shows a high selectivity for mP-gp and its potency is 20-50 times higher than that of tariquitar, another third generation P-gp inhibitor. (In Vivo) :PET scans with the Pgp substrate (R) -[11C]NSC 657799 in FVB wild-type mice pretreated i.v. with Encequidar (HM30181) (10 or 21 mg/kg) failes to show significant increases in (R) -[11C]NSC 657799 brain uptake compared with vehicle treated animals.Encequidar (HM30181) inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Encequidar (HM30181) increases the oral bioavailability of co-administered NSC 125973 by more than 12 times in rats.