Controlled drug release: new water-soluble prodrugs of an HIV protease inhibitor.
We designed and synthesized a series of highly water-soluble prodrugs of an HIV protease inhibitor, KNI-727 (1), containing tandem-linked two auxiliary units, a solubilizing moiety and a self-cleavable spacer. Prodrugs with an ionized amino group at the solubilizing moiety exhibited a remarkable increase of water-solubility (>10(4) fold) compared to the parent drug 1. These prodrugs released I not enzymatically, but chemically via an intramolecular cyclization-elimination reaction through an imide formation in physiological conditions. Diversified rates of parent drug release were observed when the chemical structure of both the solubilizing and the spacer moieties were modified. This new approach for water-soluble prodrugs will enable to control chemically the release of parent drug as well as to maintain high water-solubility.
Matsumoto
H
H
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Japan.
Sohma
Y
Y
Kimura
T
T
Hayashi
Y
Y
Kiso
Y
Y
D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility
D017320:HIV Protease Inhibitors; D011355:Prodrugs