title: Structure-activity relationship of HIV-1 protease inhibitors containing alpha-hydroxy-beta-amino acids. Detailed study of P1 site.
abstract: The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing alpha-hydroxy-beta-amino acids is discussed. We demonstrated that substituent groups on the P1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent [IC90 (CEM/HIV-1 IIIB) 27 nM] and showed good pharmacokinetics in rats.
authors.affiliation: Exploratory Chemistry Research Laboratory, Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Takashiro
authors.forename: I
authors.initials: I
authors.lastname: Hayakawa
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: I
authors.initials: I
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Shibayama
authors.forename: A
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yabe
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D017320:HIV Protease Inhibitors; D010649:Phenylalanine