MISC

査読有り
2004年1月

Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O -> N intramolecular acyl migration: design, synthesis and kinetic study

BIOORGANIC & MEDICINAL CHEMISTRY
  • Y Hamada
  • ,
  • H Matsumoto
  • ,
  • S Yamaguchi
  • ,
  • T Kimura
  • ,
  • Y Hayashi
  • ,
  • Y Kiso

12
1
開始ページ
159
終了ページ
170
記述言語
英語
掲載種別
DOI
10.1016/j.bmc.2003.10.026
出版者・発行元
PERGAMON-ELSEVIER SCIENCE LTD

To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-727, a potent small-sized dipeptide-type HIV-1 protease inhibitor consisting of an Apns-Dmt core (Apns; allophenylnorstatine, Dmt; (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid) as inhibitory machinery. These prodrugs contained an O-acyl peptidomimetic structure with an ionized amino group leading to an increase in water-solubility, and were designed to regenerate the corresponding parent drugs based on the O --> N intramolecular acyl migration reaction via a five-membered ring intermediate at the alpha-hydroxy-beta-amino acid residue, that is Apns. The synthetic prodrug 3a improved the water-solubility (13 mg/mL) more than 8000-fold in comparison with the parent compound, which is the practically acceptable value as water-soluble drug. Furthermore, to understand the structural effects of the O-acyl moiety on the migration rate, we evaluated several phenylacetyl-type and benzoyl-type prodrugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly under aqueous conditions from slightly acidic to basic pH at 37 degreesC. (C) 2003 Elsevier Ltd. All rights reserved.

Web of Science ® 被引用回数 : 41

リンク情報
DOI
https://doi.org/10.1016/j.bmc.2003.10.026
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000188113400017&DestApp=WOS_CPL

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