Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94

Abstract

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 μM [3H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC50s of 0.24 μM and 0.41 μM, and had a competitive profile with Ki of 0.2 μM against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1–10 μM of 264W94 rapidly decreased uptake of 3mM TC by 24–39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-75Se-homocholic acid taurine (75SeHCAT; quantitated in feces), with ED30 of 0.02 mg/kg bid. 75SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of 75SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic cholesterol 7α-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03–1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL cholesterol up to 61%.In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.

Keywords

• CAS RN 178961-24-5
• human ileal apical sodium-dependent bile acid co-transporter
• brush border membrane vesicles
• cholesterol 7α-monooxygenase
• hypocholesterolemic agents
• 75Se-homocholic acid taurine