Torcetrapib
Torcetrapib increases large HDL particles more than a novel FXR antagonist in a hamster model of dyslipidemia (Pharmacol Res Perspect 2018)
Original title: Antidyslipidemic potential of a novel farnesoid X receptor antagonist in a hamster model of dyslipidemia: Comparative studies of other nonstatin agents
Researchers tested a novel farnesoid X receptor (FXR) antagonist, compound-T1, which selectively inhibited chenodeoxycholic acid-induced FXR activation (IC50 2.1 nmol per L), in a hamster model of diet-induced hyperlipidemia, comparing it against the nonstatin lipid-modulating agents ezetimibe, cholestyramine, and torcetrapib. Compound-T1 at 6 mg per kg per day raised HDL cholesterol by 22.2% and lowered non-HDL cholesterol by 43.6% and triglycerides by 31.1%, while also increasing hepatic cholesterol 7-alpha-hydroxylase expression and fecal bile acid excretion. The hamster model reflected known clinical effects of the comparator agents, and torcetrapib specifically increased large HDL particles to a greater extent than compound-T1, distinguishing the CETP-inhibition mechanism from the bile-acid and cholesterol-catabolism mechanism of the FXR antagonist.
Original abstract
We attempted to clarify the therapeutic capability of antagonists of the farnesoid X receptor (FXR), a nuclear receptor that regulates lipid and bile acid metabolism. Herein, we report the antidyslipidemic effects of a novel synthesized FXR antagonist, compound-T1, utilizing a dyslipidemic hamster model. Compound-T1 selectively inhibited chenodeoxycholic acid-induced FXR activation (IC 50, 2.1 nmol·L-1). A hamster model of diet-induced hyperlipidemia was prepared to investigate the antidyslipidemic effects of compound-T1 through comparative studies of the nonstatin lipid-modulating agents ezetimibe, cholestyramine, and torcetrapib. In the hamster model, compound-T1 (6 mg·kg-1·day-1, p.o.) increased the level of plasma high-density lipoprotein (HDL)-cholesterol (+22.2%) and decreased the levels of plasma non-HDL-cholesterol (-43.6%) and triglycerides (-31.1%). Compound-T1 also increased hepatic cholesterol 7α-hydroxylase expression and fecal bile acid excretion, and decreased hepatic cholesterol content. Moreover, the hamster model could reflect clinical results of other nonstatin agents. Torcetrapib especially increased large HDL particles compared with compound-T1. Additionally, in the human hepatoma Huh-7 cells, compound-T1 enhanced apolipoprotein A-I secretion at a concentration close to its IC 50 value for FXR. Our results indicated the usefulness of the hamster model in evaluating FXR antagonists and nonstatin agents. Notably, compound-T1 exhibited beneficial effects on both blood non-HDL-cholesterol and HDL-cholesterol, which are thought to involve enhancement of cholesterol catabolism and apolipoprotein A-I production. These findings aid the understanding of the antidyslipidemic potential of FXR antagonists with a unique lipid and bile acid modulation.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.