Xie Haibo, Chen Gang, Young Robert N
Department of Chemistry, Simon Fraser University , Burnaby, British Columbia V5A 1S6, Canada.
J Med Chem. 2017 Aug 24;60(16):7012-7028. doi: 10.1021/acs.jmedchem.6b00951. Epub 2017 Aug 10.
A dual-action bone-targeting prodrug has been designed, synthesized, and evaluated for in vitro and in vivo metabolic stability, in vivo tissue distribution, and rates of release of the active constituents after binding to bones through the use of differentially double-labeled derivatives. The conjugate (general structure 7) embodies the merger of a very potent and proven anabolic selective agonist of the prostaglandin EP4 receptor, compound 5, and alendronic acid, a potent inhibitor of bone resorption, optimally linked through a differentially hydrolyzable linker unit, N-4-carboxymethylphenyl-methyloxycarbonyl-leucinyl-argininyl-para-aminophenylmethylalcohol (Leu-Arg-PABA). Optimized conjugate 16 was designed so that esterase activity will liberate 5 and cathepsin K cleavage of the Leu-Arg-PABA element will liberate alendronic acid. Studies with doubly radiolabeled 16 provide a proof-of-concept for the use of a cathepsin K cleavable peptide-linked conjugate for targeting of bisphosphonate prodrugs to bone and slow release liberation of the active constituents in vivo. Such conjugates are potential therapies for the treatment of bone disorders such as osteoporosis.
一种双作用骨靶向前药已被设计、合成，并通过使用差异双标记衍生物对其体外和体内代谢稳定性、体内组织分布以及与骨结合后活性成分的释放速率进行了评估。该缀合物（通用结构7）体现了一种非常强效且经过验证的前列腺素EP4受体合成代谢选择性激动剂化合物5与阿仑膦酸（一种强效骨吸收抑制剂）的结合，通过一个差异可水解连接单元N - 4 - 羧甲基苯基 - 甲氧基羰基 - 亮氨酰 - 精氨酰 - 对氨基苯甲醇（Leu - Arg - PABA）实现了最佳连接。优化后的缀合物16的设计使得酯酶活性能够释放5，而组织蛋白酶K对Leu - Arg - PABA元件的切割将释放阿仑膦酸。对双放射性标记的16进行的研究为使用组织蛋白酶K可切割的肽连接缀合物将双膦酸盐前药靶向骨并在体内缓慢释放活性成分提供了概念验证。此类缀合物是治疗骨质疏松等骨疾病的潜在疗法。
