Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use
Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use
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DOI：
10.1016/j.bone.2021.116289
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发表时间：
2022-03-01
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：
Ebetino, Frank H.;Sun, Shuting;Russell, R. Graham G.
双膦酸盐 ((H2O)(2)P(O)(CRRP)-R-1-P-2(O)(OH)(2), BPs）在 20 世纪 60 年代首次被证明可以抑制骨吸收，但直到 30 年后，人们才对其不同的化学结构和生物活性之间的关系进行了详细的分子理解。在 20 世纪 90 年代和 2000 年代，几种 R-2 侧链含氮的强效双膦酸盐 (N-BP) 被批准用于临床，包括阿仑膦酸盐、利塞膦酸盐、伊班膦酸盐和唑来膦酸盐。这些药物现在大多是仿制药，并且仍然是几种主要骨相关疾病的主要治疗方法，包括骨质疏松症和与骨转移相关的骨骼相关事件。该领域化学的早期发展很大程度上是经验性的，只有一些与磷酸钙强结合相关的常见结构特征是清楚的。进一步发展结构-活性关系来解释体内更显着的药理学差异的尝试最初似乎没有结论，并且经过多年的研究才出现了对破骨细胞和巨噬细胞的细胞作用机制的证据。当更简单的二磷酸盐通过体内形成 ATP 的 P-C-P 衍生物首次显示出对破骨细胞的细胞内作用时，突破就出现了。 20 世纪 80 年代和 90 年代大量含氮二膦酸盐的合成和生物学评价带来了一个关键发现：这些更复杂的类似物对破骨细胞的抗吸收作用主要来自于它们作为法尼基二磷酸合酶 (FDPS/FPPS) 抑制剂的效力。这种胆固醇生物合成甲羟戊酸途径中的关键分支点酶对于类异戊二烯脂质的生成非常重要，类异戊二烯脂质可用于破骨细胞功能所必需的小 GTP 结合蛋白的翻译后修饰。从那时起，人们更加清楚地认识到，各种双膦酸盐对骨的总体药理作用取决于两个关键特性：对骨矿物质的亲和力以及对骨细胞内生化靶点（特别是 FDPS）的抑制作用。详细的酶-配体晶体结构分析始于 2000 年代初，基于甲羟戊酸途径中该靶标以及破骨细胞和其他细胞中相关酶的相互作用，我们对结构-活性关系的理解不断取得进展，至今仍然是研究工作的重点。此外，虽然双膦酸盐药物类别的许多成员具有共同的特性，但现在更清楚的是，通过化学修饰来产生这些特性的变化可能允许针对不同用途定制BP。因此，随着对该药物类别的新潜在机会的认识不断增长，人们不断开发出新的化学物质，以方便获得越来越多的双膦酸盐品种。双膦酸盐的磷酸钙结合机制在其他药物靶向骨骼方面的潜在新用途，以及对其他细胞靶点（甚至在非骨骼部位）的影响，继续引起该研究领域科学家的兴趣。
The bisphosphonates ((HO)(2)P(O)(CRRP)-R-1-P-2(O)(OH)(2), BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R-2 side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme-ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day. In addition, while many members of the bisphosphonate drug class share common properties, now it is more clear that chemical modifications to create variations in these properties may allow customization of BPs for different uses.Thus, as the appreciation for new potential opportunities with this drug class grows, new chemistry to allow ready access to an ever-widening variety of bisphosphonates continues to be developed. Potential new uses of the calcium phosphate binding mechanism of bisphosphonates for the targeting of other drugs to the skeleton, and effects discovered on other cellular targets, even at non-skeletal sites, continue to intrigue scientists in this research field.