Pyrido [1,2a] indole derivatives identified as novel non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1

Pyrido [1,2a] indole derivatives were identified as potent inhibitors of hu man immunodeficiency virus type 1 (HIV-1) replication during a random scree ning programme. The compounds showed no antiviral activity against HIV-2 or in cells chronically infected with HIV-1, but had good inhibitory effect a gainst purified HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore classified as non-nucleoside RT inhibitors (NNRTI). The syn thesis of additional compounds of the same class revealed a structure-activ ity relationship. The most potent compound of the series, BCH-1, had simila r antiviral activity to the licensed NNRTI nevirapine against laboratory st rains of HIV-1 cultured in cell lines and primary clinical isolates of HIV- 1 cultured in peripheral blood mononuclear cells. However, BCH-1 showed gre ater cytotoxicity, providing a narrow selectivity index in the order of 35. BCH-1 had equivalent antiviral activity against viruses resistant to the n ucleoside RT inhibitors zidovudine, didanosine and lamivudine and maintaine d better activity (less than threefold change in IC50) than nevirapine agai nst viruses resistant to a range of NNRTIs with the single amino acid chang es L100I, K103N, E138K or Y181C in the RT. Viruses with single V106A or Y18 8C amino acid changes showed five- and 10-fold resistance to BCH-1, respect ively, in contrast to nevirapine, which had a >100-fold change in IC50. How ever, virus with both V106A and Y188C amino acid changes showed higher leve l resistance (>15-fold) to BCH-1. Virus with >10-fold resistance to BCH-1 w as rapidly selected for after growth in increasing concentrations of compou nd and was shown to be cross-resistant to nevirapine. Sequencing of this vi rus 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 le ad to identify more selective compounds.