Synthesis, modelling and kinetic assays of potent inhibitors of purple acid phosphatase

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• 作者：Siti Hajar Mohd-Pahmi^a ; Waleed M. Hussein^a ; Gerhard Schenk^a ; ^b ; Ross P. McGeary^a ; ^c ; ^{r.mcgeary@uq.edu.au"" rel=""nofollow}
• 关键词：Purple acid phosphatase ; PAP ; Phosphonate ; Osteoporosis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 May 2011
• 年：2011
• 卷：21
• 期：10
• 页码：3092-3094
• 全文大小：380 K

文摘

Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. Based on a previous lead compound and rational drug design, acyl derivatives of α-aminonaphthylmethylphosphonic acid were synthesised and tested as PAP inhibitors. Kinetic analysis showed that they are good PAP inhibitors whose potencies improve with increasing acyl chain length. Maximum potency is reached when the number of carbons in the acyl chain is between 12 and 14. The most potent inhibitor of red kidney bean PAP is the dodecyl-derivative with K_ic = 5 μM, while the most potent pig PAP inhibitor is the tetradecyl-derivative with K_ic = 8 μM, the most potent inhibitor of a mammalian PAP yet reported.