- New water-soluble prodrugs of HIV protease inhibitors based on O→N intramolecular acyl migration
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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 α-hydroxy-β-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300 mg/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°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 t1/2 value of 32 h that may not be suitable for practical use.
- Hamada, Yoshio,Ohtake, Jun,Sohma, Youhei,Kimura, Tooru,Hayashi, Yoshio,Kiso, Yoshiaki
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p. 4155 - 4167
(2007/10/03)
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- Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere
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We designed and synthesized a new class of peptidomimetic human immunodeficiency virus protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structure-activity relationship study of HIV-1 protease inhibition, enzyme selectivity for other aspartyl proteases, the antiviral activity and pharmacokinetics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreover, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178,h: JE-2179).
- Mimoto, Tsutomu,Hattori, Naoko,Takaku, Haruo,Kisanuki, Sumitsugu,Fukazawa, Tominaga,Terashima, Keisuke,Kato, Ryohei,Nojima, Satoshi,Misawa, Satoru,Ueno, Takamasa,Imai, Junya,Enomoto, Hiroshi,Tanaka, Shigeki,Sakikawa, Hiroshi,Shintani, Makoto,Hayashi, Hideya,Kiso, Yoshiaki
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p. 1310 - 1326
(2007/10/03)
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