147359-13-5Relevant academic research and scientific papers
1,1-Bisphosphonate squalene synthase inhibitors: Interplay between the isoprenoid subunit and the diphosphate surrogate
Magnin,Biller,Dickson Jr.,Logan,Lawrence,Chen,Sulsky,Ciosek Jr.,Harrity,Jolibois,Kunselman,Rich,Slusarchyk
, p. 2596 - 2605 (1995)
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.
Bisphosphonate squalene synthetase inhibitors and method
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, (2008/06/13)
Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents are provided which have the structure STR1 and analogs thereof, wherein R1, R2, R3 and R4 are the same or different and are H, lower alkyl, a metal ion or a prodrug ester; R5 is H, halogen or lower alkyl; Zq is substituted alkenyl, substituted alkynyl, mixed alkenyl-alkynyl or substituted phenylalkyl or, phenylalkenyl or phenylalkynyl, or alkyl, including all stereoisomers thereof. New methods for using such compounds to inhibit cholesterol biosynthesis are also provided.
