An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

1,1-Bisphosphonate squalene synthase inhibitors: interplay between the isoprenoid subunit and the diphosphate surrogate.

Inhibitors of squalene synthase have the potential to be superior cholesterol-lowering agents. We previously disclosed that lipophilic 1,1-bisphosphonates I are potent squalene synthase inhibitors and orally active cholesterol-lowering agents in animal models (Ciosek, C. P., Jr.; et al. J. Biol. Chem. 1993, 268, 24832-24837). In this paper, we describe modifications to the bisphosphonate moiety, in an attempt to reduce the number of acidic functions contained in these inhibitors. Replacing one of the acidic groups with a methyl (II, R2 = CH3) results in potent inhibitors when paired with a close mimic of the naturally occurring farnesyl moiety (R1 = farnesylethyl) but not when paired with the shorter isoprene surrogates (R1 = geranylethyl or 4-biphenylpropyl). In contrast, all three corresponding bisphosphonates I are potent squalene synthase inhibitors. Inhibitory potency is recovered with the shorter isoprene surrogates when R2 is CH2OH or CH2OCH3. It is proposed that these R2 groups serve as hydrogen bond acceptors with the active site of the enzyme. The properties of these compounds as cholesterol biosynthesis inhibitors in rats are described, and synthetic routes to these and related compounds are detailed.

A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors.

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.

Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo.

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene at the final branchpoint of the cholesterol biosynthetic pathway. We report herein that isoprenyl 1,1-bisphosphonates and related analogs are potent inhibitors of rat microsomal squalene synthase (I50 = 0.7-32 nM). In addition, members of this family are potent inhibitors of cholesterol biosynthesis in rats on intravenous and oral dosing, as well as cholesterol lowering agents in rats and hamsters. Significant inhibition of cholesterol biosynthesis in rats by lovastatin occurs with a concomitant inhibition of dolichol and coenzyme-Q9 synthesis. In contrast, bisphosphonate 4 has no effect on dolichol and coenzyme-Q9 biosynthesis in rats under conditions where cholesterol biosynthesis is > 90% inhibited.