title: A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity.
abstract: A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: T J
authors.initials: TJ
authors.lastname: Tucker
authors.forename: W C
authors.initials: WC
authors.lastname: Lumma
authors.forename: L S
authors.initials: LS
authors.lastname: Payne
authors.forename: J M
authors.initials: JM
authors.lastname: Wai
authors.forename: S J
authors.initials: SJ
authors.lastname: de Solms
authors.forename: E A
authors.initials: EA
authors.lastname: Giuliani
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: J C
authors.initials: JC
authors.lastname: Heimbach
authors.forename: J A
authors.initials: JA
authors.lastname: Zugay
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005021:Ethylamines / Q000737:chemistry / Q000494:pharmacology*; D016655:HIV Core Protein p24 / Q000032:analysis; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D005021:Ethylamines; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D011480:Protease Inhibitors; D016333:HIV Protease