Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea.
Bioorg Med Chem Lett. 2010 Nov 1;20(21):6327-30. doi: 10.1016/j.bmcl.2010.05.060. Epub 2010 May 20.
Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3·HCl (l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3·HCl intravenously, with rapid clearance of 3·HCl indicating the effective cleavage of prodrug. Compound 3·HCl (CKD-516) has now been progressed to phase 1 clinical trial.
前药已被证明在提高疏水性药物的水溶性方面非常有用，从而在不需要特殊辅料的情况下提高体内疗效。对以前鉴定出的强效微管聚合抑制剂和对各种癌细胞系具有细胞毒性的 1 的一些氨基酸前药的体外和体内评价导致发现了 3·HCl（连接 L-缬氨酸），它在携带人类癌症的小鼠异种移植中非常有效。在大鼠中的药代动力学分析表明，化合物 1 在静脉注射 3·HCl 后立即释放，3·HCl 的快速清除表明前药的有效裂解。化合物 3·HCl（CKD-516）现已进入 1 期临床试验。
