Discovery of a potent tubulin polymerization inhibitor: Synthesis and evaluation of water-soluble prodrugs of benzophenone analog |
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Authors: | Jaekwang Lee Suyeal Bae Seo-hee Lee Hojin Choi Young Hoon Kim Soo Jin Kim Gyu Tae Park Seung Kee Moon Dal-Hyun Kim Sungsook Lee Soon Kil Ahn Nam Song Choi Kyung Joo Lee |
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Affiliation: | 1. Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea;2. Division of Life Science, University of Incheon, Incheon 406-772, Republic of Korea |
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Abstract: | 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. |
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