title: Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase.
abstract: In vitro evaluation of a large chemical library of pharmacologically acceptable prototype compounds in a high-capacity, cellular-based screening system has led to the discovery of another family of human immunodeficiency virus type 1 (HIV-1) inhibitors. Through optimization of a lead compound, several alpha-anilinophenylacetamide (alpha-APA) derivatives have been identified that inhibit the replication of several HIV-1 strains (IIIB/LAI, RF, NDK, MN, HE) in a variety of host cell types at concentrations that are 10,000- to 100,000-fold lower than their cytotoxic concentrations. The IC50 of the alpha-APA derivative R 89439 for HIV-1 cytopathicity in MT-4 cells was 13 nM. The median 90% inhibitory concentration (IC90) in a variety of host cells was 50-100 nM. Although these alpha-APA derivatives are active against a tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione-(TIBO)-resistant HIV-1 strain, they do not inhibit replication of HIV-2 (strains ROD and EHO) or simian immunodeficiency virus (strains Mac251, mndGB1, and agm3). An HIV-1 strain containing the Tyr181-->Cys mutation in the reverse transcriptase region displayed reduced sensitivity. alpha-APA derivative R 89439 inhibited virion and recombinant reverse transcriptase of HIV-1 but did not inhibit that of HIV-2. Reverse transcriptase inhibition depended upon the template/primer used. The relatively uncomplicated synthesis of R 89439, its potent anti-HIV-1 activity, and its favorable pharmacokinetic profile make R 89439 a good candidate for clinical studies.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: K
authors.initials: K
authors.lastname: Andries
authors.forename: Z
authors.initials: Z
authors.lastname: Debyser
authors.forename: P
authors.initials: P
authors.lastname: Van Daele
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: P
authors.initials: P
authors.lastname: Stoffels
authors.forename: K
authors.initials: K
authors.lastname: De Vreese
authors.forename: R
authors.initials: R
authors.lastname: Woestenborghs
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: C G
authors.initials: CG
authors.lastname: Janssen
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000098:Acetophenones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents; D016655:HIV Core Protein p24 / Q000378:metabolism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008297:Male; D018894:Reverse Transcriptase Inhibitors; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000081:Acetamides; D000098:Acetophenones; D000814:Aniline Compounds; D000998:Antiviral Agents; D016655:HIV Core Protein p24; D018894:Reverse Transcriptase Inhibitors; C080073:loviride; D054303:HIV Reverse Transcriptase