title: Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design.
abstract: By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.
authors.affiliation: Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: P M
authors.initials: PM
authors.lastname: Fitzgerald
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: B M
authors.initials: BM
authors.lastname: McKeever
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: J C
authors.initials: JC
authors.lastname: Quintero
authors.forename: J A
authors.initials: JA
authors.lastname: Zugay
authors.forename: T J
authors.initials: TJ
authors.lastname: Tucker
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D017320:HIV Protease Inhibitors; D009025:Morpholines; D010455:Peptides; D011480:Protease Inhibitors; C072111:L 689502; D016333:HIV Protease