Discovery of a potent tubulin polymerization inhibitor: synthesis and evaluation of water-soluble prodrugs of benzophenone analog

  • Bioorg Med Chem Lett. 2010 Nov 1;20(21):6327-30. doi: 10.1016/j.bmcl.2010.05.060.
Jaekwang Lee  1 ,  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
Affiliations
  • 1. Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea.
PMID: 20850313 DOI: 10.1016/j.bmcl.2010.05.060
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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