title: Structure-activity relationship of HIV-1 protease inhibitors containing AHPBA. Part III: Modification of P2 site.
abstract: The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing AHPBA (3-amino-2-hydroxy-4-phenylbutanoic acid) is discussed. In order to solve the problem of poor oral bioavailability, small-sized dipeptide HIV-1 protease inhibitors containing cyclic urethanes or benzamides at the P2 site were designed and prepared. The substitution patterns of the benzamides contributed significantly to their HIV-1 PR inhibitory activities, and it was shown that the choice of P2-residues was very important. Highly potent inhibitors possessing subnanomolar IC50 values and exhibiting good antiviral potency have been identified. In this class, inhibitor 18 was the most potent (IC90 (CEM/HIV-1 IIIB) 0.11 microM) and showed good oral bioavailability in dogs.
authors.affiliation: Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Takashiro
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Nitta
authors.forename: A
authors.initials: A
authors.lastname: Kasuya
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Ozawa
authors.forename: R
authors.initials: R
authors.lastname: Yagi
authors.forename: T
authors.initials: T
authors.lastname: Nishigaki
authors.forename: T
authors.initials: T
authors.lastname: Shibayama
authors.forename: A
authors.initials: A
authors.lastname: Nakagawa
authors.forename: A
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Yabe
mesh_terms: D000818:Animals; D001682:Biological Availability; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010654:Phenylbutyrates / Q000737:chemistry*; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid