title: Pyrido [1,2a] indole derivatives identified as novel non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1.
abstract: Pyrido [1,2a] indole derivatives were identified as potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication during a random screening programme. The compounds showed no antiviral activity against HIV-2 or in cells chronically infected with HIV-1, but had good inhibitory effect against purified HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore classified as non-nucleoside RT inhibitors (NNRTI). The synthesis of additional compounds of the same class revealed a structure-activity relationship. The most potent compound of the series, BCH-1, had similar antiviral activity to the licensed NNRTI nevirapine against laboratory strains of HIV-1 cultured in cell lines and primary clinical isolates of HIV-1 cultured in peripheral blood mononuclear cells. However, BCH-1 showed greater cytotoxicity, providing a narrow selectivity index in the order of 35. BCH-1 had equivalent antiviral activity against viruses resistant to the nucleoside RT inhibitors zidovudine, didanosine and lamivudine and maintained better activity (less than threefold change in IC50) than nevirapine against viruses resistant to a range of NNRTIs with the single amino acid changes L100I, K103N, E138K or Y181C in the RT. Viruses with single V106A or Y188C amino acid changes showed five- and 10-fold resistance to BCH-1, respectively, in contrast to nevirapine, which had a > 100-fold change in IC50. However, virus with both V106A and Y188C amino acid changes showed higher level resistance (> 15-fold) to BCH-1. Virus with > 10-fold resistance to BCH-1 was rapidly selected for after growth in increasing concentrations of compound and was shown to be cross-resistant to nevirapine. Sequencing of this virus revealed two amino acid changes at positions 179 (V to D) and 181 (Y to C) in the RT. BCH-1 represents a new class of NNRTI, which may act as a lead to identify more selective compounds.
authors.affiliation: MRC Collaborative Centre, London, UK. d-taylor@mrc.nimr.ac.uk
authors.forename: D L
authors.initials: DL
authors.lastname: Taylor
authors.forename: P S
authors.initials: PS
authors.lastname: Ahmed
authors.forename: P
authors.initials: P
authors.lastname: Chambers
authors.forename: A S
authors.initials: AS
authors.lastname: Tyms
authors.forename: J
authors.initials: J
authors.lastname: Bedard
authors.forename: J
authors.initials: J
authors.lastname: Duchaine
authors.forename: G
authors.initials: G
authors.lastname: Falardeau
authors.forename: J F
authors.initials: JF
authors.lastname: Lavallée
authors.forename: W
authors.initials: W
authors.lastname: Brown
authors.forename: R F
authors.initials: RF
authors.lastname: Rando
authors.forename: T
authors.initials: T
authors.lastname: Bowlin
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D016133:Polymerase Chain Reaction; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D007211:Indoles; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase