New water-soluble prodrugs of HIV protease inhibitors based on O-->N intramolecular acyl migration.
To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs, which contained an O-acyl peptidomimetic structure with an ionized amino group leading to the increase of water-solubility, were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction at the alpha-hydroxy-beta-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300mg/mL) more than 4000-fold in comparison with the parent compounds, which is the practically acceptable value as water-soluble drugs. 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 in the aqueous condition from slightly acidic to basic pH at 37 degrees C, with the suitable migration rate, via a five-membered ring intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir, a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to ritonavir probably through a six-membered ring intermediate, with the t(1/2) value of 32h that may not be suitable for practical use.
Hamada
Yoshio
Y
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, Japan.
Ohtake
Jun
J
Sohma
Youhei
Y
Kimura
Tooru
T
Hayashi
Yoshio
Y
Kiso
Yoshiaki
Y
D000215:Acylation; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011355:Prodrugs; C077822:kynostatin 272