title: HIV-1 protease inhibitors based on hydroxyethylene dipeptide isosteres: an investigation into the role of the P1' side chain on structure-activity.
abstract: A systematic investigation was undertaken to determine the role of the P1' sidechain in a series of hydroxyethylene isostere based inhibitors of HIV-1 protease. Substitution and homologation of the benzyl P1' side chain of the Phe-Phe isostere based pseudo peptides 1 (L-682,679) and 2 (L-685,434) with various heteroalkyl groups leads to a series of extremely potent inhibitors of the enzyme. Several examples of the most potent inhibitors were very effective in an ex vivo cell based viral spread assay using human H9 T-lymphocytes and the IIIb isolate of HIV-1. Compound 19 is 120 times more potent than 1 and 16 times more potent than 2 in inhibiting the spread of infection in this assay.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: S D
authors.initials: SD
authors.lastname: Young
authors.forename: L S
authors.initials: LS
authors.lastname: Payne
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: N
authors.initials: N
authors.lastname: Gaffin
authors.forename: T A
authors.initials: TA
authors.lastname: Lyle
authors.forename: S F
authors.initials: SF
authors.lastname: Britcher
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: T H
authors.initials: TH
authors.lastname: Schultz
authors.forename: A A
authors.initials: AA
authors.lastname: Deana
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005030:Ethylenes / Q000138:chemical synthesis / Q000494:pharmacology*; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000201:enzymology* / Q000254:growth & development; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010710:Phosphates / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000382:microbiology
chemical_list: D000998:Antiviral Agents; D004151:Dipeptides; D005030:Ethylenes; D017320:HIV Protease Inhibitors; D007211:Indoles; D009842:Oligopeptides; D010710:Phosphates; D011480:Protease Inhibitors; C070944:L 682679; C074651:L 685434; C067254:hydroxyethylene; D016333:HIV Protease