Effect of the acyl groups on O-->N acyl migration in the water-soluble prodrugs of HIV-1 protease inhibitor.
To improve the low water-solubility of HIV-1 protease inhibitors KNI-272, -279 and -727, we previously reported the water-soluble prodrugs of these inhibitors based on O-->N intramolecular acyl migration reaction. These prodrugs were rapidly converted to the corresponding parent drugs under physiological conditions. To understand the steric and electrostatic effects of O-acyl moiety on the migration rate, we examined several types of prodrug. A remarkably slow migration was observed in the benzoyl-type prodrugs, and Hammett plot of migration rate constants of p-substituted benzoyl-type prodrugs gave a linear free energy relationship.
Hamada
Yoshio
Y
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Matsumoto
Hikaru
H
Kimura
Tooru
T
Hayashi
Yoshio
Y
Kiso
Yoshiaki
Y
D000215:Acylation; D001565:Benzoates / Q000737:chemistry; D004355:Drug Stability; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010642:Phenoxyacetates / Q000737:chemistry; D010648:Phenylacetates / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012995:Solubility; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014867:Water
D001565:Benzoates; D017320:HIV Protease Inhibitors; D010642:Phenoxyacetates; D010648:Phenylacetates; D011355:Prodrugs; D014867:Water