1,1-Bisphosphonate Squalene Synthase Inhibitors: Interplay Between the Isoprenoid Subunit and the Diphosphate Surrogate
JOURNAL OF MEDICINAL CHEMISTRY(1995)
Abstract
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, R(2) = CH3) results in potent inhibitors when paired with a close mimic of the naturally occurring farnesyl moiety (R(1) = farnesylethyl) but not when paired with the shorter isoprene surrogates (R(1) = 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 R(2) is CH2OH or CH2OCH3. It is proposed that these R(2) groups serve as hydrogen bond accepters 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.
MoreTranslated text
Key words
isoprenoid subunit,inhibitors
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined