title: Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O-->N intramolecular acyl migration: Design, synthesis and kinetic study.
abstract: 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 degrees C.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.forename: Hikaru
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Tooru
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D000215:Acylation; D004151:Dipeptides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D012995:Solubility / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics; D014867:Water / Q000737:chemistry*
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; C435823:KNI-727; D011355:Prodrugs; D013844:Thiazoles; D014867:Water