A Novel Series of Highly Potent Benzimidazole-Based Microsomal Triglyceride Transfer Protein Inhibitors

Abstract

A series of benzimidazole-based analogues of the potent MTP inhibitor BMS-201038 were discovered. Incorporation of an unsubstituted benzimidazole moiety in place of a piperidine group afforded potent inhibitors of MTP in vitro which were weakly active in vivo. Appropriate substitution on the benzimidazole ring, especially with small alkyl groups, led to dramatic increases in potency, both in a cellular assay of apoB secretion and especially in animal models of cholesterol lowering. The most potent in this series, 3g (BMS-212122), was significantly more potent than BMS-201038 in reducing plasma lipids (cholesterol, VLDL/LDL, TG) in both hamsters and cynomolgus monkeys.

CD1d-mediated Presentation of Endogenous Lipid Antigens by Adipocytes Requires Microsomal Triglyceride Transfer Protein

“…After 24 h of co-culture, the supernatant was stored at Ϫ80°C until analysis of IFN␥ and IL4 cytokine levels. For MTP inhibition assay, 13 M BMS212122, a specific chemical inhibitor of MTP-mediated lipid transfer (38), was added to the 3T3L-L1 cells on day 0 of the differentiation. On day 7 the inhibitor was washed away and (pre)adipocytes were co-cultured with DN32.D3 hybridoma cells (24 h).…”

Lomitapide: a novel drug for homozygous familial hypercholesterolemia

“…It was also noted that the secretion of ApoB from cultured HepG2 cells was significantly reduced compared with that in untreated cells [54].…”

“…In cell culture studies, the IC 50 for inhibition of ApoB secretion by lomitapide was much lower than that for ApoAI secretion (0.8 nM vs 6.5 µM), indicating that the compound is a highly selective inhibitor of ApoB secretion [54]. It was also noted that the secretion of ApoB from cultured HepG2 cells was significantly reduced compared with that in untreated cells [54].…”

Evolutionary conservation of drug action on lipoprotein metabolism-related targets

“…Triton treatment also increases the plasma levels of cholesterol and LDL (37). This model has been used successfully in mice and rats for the identification of several lipid metabolism modulators, such as squalene synthase inhibitors (38) and MTP inhibitors (39,40). Figure 5 shows that CHGN005, administered at 50 mg/kg by intravenous injection, decreases cholesterol and triglycerides in the Triton model.…”