title: Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic.
abstract: A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized. Phenylnorstatine [Pns; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] and the 2S diastereomer, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) were effective transition-state mimics, and incorporation of Pns-Pro or Apns-Pro at the P1-P1' site gave potent and specific HIV-1 protease inhibitors. In the inhibitory assays, the chemically synthesized [Ala67,95] HIV-1 protease was used.
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mimoto
authors.forename: J
authors.initials: J
authors.lastname: Imai
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.forename: O
authors.initials: O
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Kisanuki
authors.forename: Y
authors.initials: Y
authors.lastname: Nagano
authors.forename: M
authors.initials: M
authors.lastname: Shintani
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Sakikawa
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017320:HIV Protease Inhibitors; D008969:Molecular Sequence Data; D010654:Phenylbutyrates / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; D011480:Protease Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid