Chemical and Pharmaceutical Bulletin p. 1310 - 1326 (2000)
Update date:2022-08-03
Topics:
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
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).
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