alpha-Phosphonosulfonic acids: Potent and selective inhibitors of squalene synthase
alpha-Phosphonosulfonic acids: Potent and selective inhibitors of squalene synthase
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DOI：
10.1021/jm9507340
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发表时间：
1996-02-02
影响因子：
7.3
通讯作者：
Ciosek, CP
中科院分区：
文献类型：
--
作者：
Magnin, DR;Biller, SA;Ciosek, CP
Inhibitors of squalene synthase have recently received considerable attention in the search for new antihypercholesterolemic agents. 1 We disclose herein the discovery of a new family of in vivo active squalene synthase inhibitors: the R-phosphonosulfonic acids. We previously reported that lipophilic 1, 1-bisphosphonates were potent inhibitors of squalene synthase and effective cholesterol-lowering agents in animal models. 2 1, 1-Bisphosphonate inhibitors were designed as mimetics of the putative ion pair intermediate formed from farnesyl diphosphate (FPP) in the initial step of the squalene synthase reaction. 3 The bisphosphonate function served as a stable surrogate for the diphosphate moiety. Although the bisphosphonates were potent cholesterol-lowering agents, they possessed several pharmacological properties which warranted further improvement. The R-phosphonosulfonic acid (R-PSA) inhibitors were developed to address these issues. Prototype 1, 1-bisphosphonate 2 elevated plasma transaminase levels (ALT and AST) in mice when administered at a single iv dose of 20 mg/kg (see Figure 1), an indication of hepatotoxicity. 4 Disposition studies with [14C]-25 in rats revealed that there was significant retention of radioactivity in bone and liver tissue 72 h after an intravenous dose. 6 The retention in bone was consistent with what is known about the bisphosphonate inhibitors of bone resorption. 7 Accumulation of inhibitor and metabolites in the liver may have contributed to the hepatotoxicity observed for 2. In addition, 2 has low oral absorption in rats (1.3%). 8 We proposed that both the tissue retention and low oral absorption were due to the highly charged nature of the bisphosphonate moiety (a tetraacid), which would make it difficult for the inhibitor to traverse cellular membranes. Accordingly, we embarked on a search for a diphosphate surrogate with fewer acidic groups. 9 A sulfonic acid can be considered to be an isostere of a phosphonic acid. The tetrahedral geometry and the interatomic distances of an alkyl sulfonic acid are very close to that of a phosphonic acid. 10-13 However, a sulfonate is a monoacid whereas a phosphonate is a diacid. In order to determine whether a sulfonate is a suitable replacement for a phosphonate, a series of three
