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

Article abstract of DOI:10.1021/jm00014a012

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.