Turofexorate isopropyl (WAY-362450) also demonstrates potent cholesterol and triglyceride-lowering effects in LDLR-/- mice and shows antiatherogenic activity by reducing aortic arch lesions. Oral administration of WAY-362450 in these mice leads to significant lipid reductions, and chronic dosing in an atherosclerosis model significantly diminishes aortic arch lesions. Administered to rats at 3 mg/kg (orally and intravenously), WAY-362450 displays good oral bioavailability (38%), a lengthy half-life of 25 hours, a modest volume of distribution, and low clearance (3.3 L/kg, about 10% of hepatic blood flow). Further pharmacokinetic data from studies in mice and higher species have been gathered and are to be published separately^[1].

In rat models, Turofexorate isopropyl elevates HDL cholesterol levels, whereas in hamsters, it reduces levels similarly to those observed in mice^[2].

In wild-type mice treated with 30 mg/kg of Turofexorate isopropyl, there is an induction of SHP expression, an effect not seen in FXR-/- mice. This compound significantly suppresses the expression of the CYP8B1 bile acid synthetic gene in wild-type mice, showcasing its regulatory impact on bile acid synthesis, though it has no effect on CYP8B1 gene expression in FXR-/- mice^[3].

Turofexorate isopropyl (WAY-362450) exhibits high specificity, showing no significant activation of other nuclear receptors (LXRα, LXRβ, PPARα, PPARγ, PPARδ, RXRα, RARγ, VDR, SXR, ERα, ERβ, GR, AR, MR, and PR) at concentrations up to 10 μM. In various assays, WAY-362450 strongly activates FXR, as demonstrated in FXR reporter gene assays and cell-based assays targeting FXR-regulated genes. Specifically, WAY-362450 elevates promoter activities for the human bile salt excretory pump (BSEP), human small heterodimer partner (SHP), and mouse intestinal bile acid binding protein (IBABP) genes, with EC50 values of 17, 230, and 33 nM, respectively. Moreover, at a concentration of 1 μM, it markedly induces mRNA levels for BSEP, SHP, and IBABP in human cells by 13-, 2-, and 20-fold, respectively^[1].

Turofexorate isopropyl (WAY-362450) effectively induces luciferase reporter expression with an EC50 of 16 nM and stimulates endogenous FXR gene activation in mouse AML12 cells and primary human hepatocytes^[2].