Determinants of structure-function relationships among bisphosphonates
Determinants of structure-function relationships among bisphosphonates
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DOI：
10.1016/j.bone.2007.03.002
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发表时间：
2007-05-01
期刊：
影响因子：
4.1
通讯作者：
Russell, R. Graham G.
中科院分区：
文献类型：
--
作者：
Russell, R. Graham G.
双膦酸盐是自20世纪70年代以来广泛使用的一类化合物，用于管理骨代谢疾病，例如PA. ET病和骨质疏松症。这类药物的成员共享一个共同的P-C-P骨架结构，其中C是碳，每个P是膦酸酯基团; 2个膦酸酯基团充当“骨钩”，对于结合羟基磷灰石至关重要。个别双膦酸盐表现出不同的结合羟基磷灰石和发挥不同的作用，破骨细胞。每种双膦酸盐的独特结构决定了其在治疗特定骨吸收疾病中的功效和相对效用。单个双膦酸盐的结构-功能曲线由R-1和R-2侧基决定。当R-I是羟基时，与骨的结合增强。R-2侧基主要决定双膦酸盐的抗吸收效力，但对结合有一定影响。R-2侧基中氮基团的存在与单个双膦酸盐抑制法尼基焦磷酸（FPP）合酶（甲羟戊酸途径中的主要酶）的能力相关。双膦酸盐之间的结构差异解释了所观察到的矿物质结合和抗骨吸收效力的差异，并可能反过来解释了该药物类别成员之间在效力、作用持续时间和抗骨折效力方面的一些临床差异。(C)2007年由Elsevier Inc.出版
Bisphosphonates are a chemical class of compounds in widespread use since the 1970s for the management of disorders of bone metabolism, such as Pa.-et's disease and osteoporosis. The members of this drug class share a common P-C-P backbone structure, where C is carbon and each P is a phosphonate group; the 2 phosphonate groups act as a "bone hook" and are essential for binding to hydroxyapatite. Individual bisphosphonates exhibit differential binding to hydroxyapatite and exert differential actions within osteoclasts. The unique structure of each bisphosphonate determines its efficacy and relative utility in treating specific disorders of bone resorption. The structure-function profile of individual bisphosphonates is determined by the R-1 and R-2 side groups. Binding to bone is enhanced when R-1 is a hydroxyl group. The R-2 side group predominantly determines the antiresorptive potency of the bisphosphonates but has some effect on binding. The presence of nitrogen groups within the R-2 side group is associated with the ability of an individual bisphosphonate to inhibit farnesyl pyrophosphate (FPP) synthase, a major enzyme in the mevalonate pathway. Structural differences among bisphosphonates explain the observed differences in mineral binding and antiresorptive potency and may in turn account for some of the clinical differences that have been seen in potency, duration of effect, and antifracture efficacy among members of this drug class. (C) 2007 Published by Elsevier Inc.