CP-346086 dihydrate is a potent, orally active inhibitor of microsomal triglyceride transfer protein (MTP), with an IC50 of 2.0 nM for both human and rodent MTP, effectively lowering plasma cholesterol and triglyceride levels in vivo.

MTP:2.0 nM (IC50)

CP-346086 demonstrates a dose-dependent inhibition of human microsomal triglyceride transfer protein (MTP)-mediated triglyceride transfer between vesicles across a concentration range of 0.1-1000 nM, achieving a half-maximum inhibitory concentration (IC50) of 2.0 nM. Additionally, when administered at concentrations for 24 hours, CP-346086 effectively inhibits the secretion of apolipoprotein B (apoB) and triglycerides from Hep-G2 cells, with an IC50 of 2.6 nM, without impacting the secretion of apoA-I or lipid synthesis.

Administered orally once daily for two weeks at doses ranging from 1-100 mg/kg, CP-346086 significantly lowers plasma total, VLDL, and LDL cholesterol, along with triglycerides in B6CBAF1J mice. A single oral dose of 25 mg/kg of CP-346086 markedly inhibits Tyloxapol-induced triglyceride accumulation in fasted rats, achieving near-complete suppression. Additionally, acute plasma triglyceride levels in mice are reduced following a single oral administration of CP-346086 at doses from 0.1-10 mg/kg. Dose-dependent reductions in total, VLDL, LDL cholesterol, and triglycerides were observed, with reductions of 23%, 33%, 75%, and 62% respectively at a dose of 10 mg/kg/day.