title: Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere.
abstract: 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).
authors.affiliation: Pharmaceuticals & Biotechnology Laboaratory, Japan Energy Corporation, Saitama.
authors.forename: T
authors.initials: T
authors.lastname: Mimoto
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.forename: H
authors.initials: H
authors.lastname: Takaku
authors.forename: S
authors.initials: S
authors.lastname: Kisanuki
authors.forename: T
authors.initials: T
authors.lastname: Fukazawa
authors.forename: K
authors.initials: K
authors.lastname: Terashima
authors.forename: R
authors.initials: R
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Nojima
authors.forename: S
authors.initials: S
authors.lastname: Misawa
authors.forename: T
authors.initials: T
authors.lastname: Ueno
authors.forename: J
authors.initials: J
authors.lastname: Imai
authors.forename: H
authors.initials: H
authors.lastname: Enomoto
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Sakikawa
authors.forename: M
authors.initials: M
authors.lastname: Shintani
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
mesh_terms: 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
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides