Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere.
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, 24h: JE-2179).
Mimoto
T
T
Pharmaceuticals & Biotechnology Laboaratory, Japan Energy Corporation, Saitama.
Hattori
N
N
Takaku
H
H
Kisanuki
S
S
Fukazawa
T
T
Terashima
K
K
Kato
R
R
Nojima
S
S
Misawa
S
S
Ueno
T
T
Imai
J
J
Enomoto
H
H
Tanaka
S
S
Sakikawa
H
H
Shintani
M
M
Hayashi
H
H
Kiso
Y
Y
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides