磷酸盐:第一个40年。

文章的细节

引用

复制到剪贴板

罗素RG

磷酸盐:第一个40年。

骨头。2011年7月,49(1):三分之一。doi: 10.1016 / j.bone.2011.04.022。2011年5月1日Epub。

PubMed ID

21555003 (在PubMed

]

文摘

第一个完整的出版物的生物效应diphosphonates,后来改名为磷酸盐,及时出现在1969年,40年后回顾其发展的历史及其对临床医学的影响。这期特刊的骨骼包含一系列的评论文章覆盖了这些药物的基础科学和临床方面,所写的许多科学家的一些人参与在这一领域所取得的进展。磷酸盐的发现和开发(BPs)作为主要类的药物用于治疗骨骼疾病一直是一个引人入胜的故事,和是一个范例,从基础研究到临床应用的一个成功的旅程。焦磷酸无机磷酸盐化学稳定类似物(PPi),它是研究PPi的角色作为人体的自然“软水器”控制的软组织和骨骼矿化导致了需要找到抑制剂的钙化抵抗碱性磷酸酶水解。PPi的观察和BPs不仅可以延缓羟磷灰石晶体的生长也解散促使研究抑制骨吸收的能力。尽管PPi无法做到这一点,BPs被证明是非常有效的骨吸收抑制剂,无论是在体外和体内实验系统,并最终在人类身上。更强有力的BPs合成和研究,很明显,物理化学效应不足以解释他们的生物效应,和细胞行为必须参与。尽管有很多尝试,直到1990年代,他们的生化行为被阐明。现在清楚的是,磷酸盐抑制骨吸收的选择性吸收和吸附到矿物表面的骨头,他们干扰的作用微破骨细胞。磷酸盐是由破骨细胞内化和干扰特定的生化过程。 Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (gammadelta) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved 'block-buster' status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over.

DrugBank数据引用了这篇文章

药物

Zoledronic酸

Clodronic酸

羟乙磷酸

药物靶点

药物	目标	类	生物	药理作用	行动
羟乙磷酸	ADP / ATP移位酶1	蛋白质	人类	未知的	抑制剂	细节
羟乙磷酸	ADP / ATP移位酶2	蛋白质	人类	未知的	抑制剂	细节
羟乙磷酸	ADP / ATP移位酶3	蛋白质	人类	未知的	抑制剂	细节
羟乙磷酸	Receptor-type酪氨酸受体磷酸酶年代	蛋白质	人类	未知的	抑制剂	细节
羟乙磷酸	v型质子atp酶催化亚基	蛋白质	人类	未知的	抑制剂	细节