Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1373548 | Bioorganic & Medicinal Chemistry Letters | 2010 | 4 Pages |
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.
Graphical abstractSynthesis and evaluation of various amino acid prodrugs of 1 led to the discovery of 3·HCl (R = (S)-isopropyl) which was shown to have potent antitumor efficacy in mouse xenografts. Pharmacokinetic study in rats was also described.Figure optionsDownload full-size imageDownload as PowerPoint slide