NEW ARYLPYRIDO-DIAZEPINE AND ARYLPYRIDO-THIODIAZEPINE DERIVATIVES AREPOTENT AND HIGHLY SELECTIVE HIV-1 INHIBITORS TARGETED AT THE REVERSE-TRANSCRIPTASE

A series of pyridobenzothiodiazepindioxides such as the 1-ethyl-6,8,9- trimethyl-6,11-dihydro-pyrido[2,3-f] [2,1,5]benzothiodiazepine-5,5-dio xide and arylpiridodiazepines such as the 6,7-dihydro-7-methyl-12-ethy l-pyrido[2,3-b] ido(2',3'-4,5]furo[2,3-f][1,4]diazepin-6(12H)-thio and the 6,7-dihydro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido- [2,3-4,5]thien o[2,3-f][1,4]diazepin-6(12H)-thione were found to inhibit human immuno deficiency virus type 1 [HIV-1(IIIB)] replication at a concentration o f 0.003-0.04 mu M without being cytotoxic at a 3000- to 15000-fold hig her concentration. These compounds proved effective against a variety of HIV-1 strains, including those that are resistant to 3'-azido-3' de oxythymidine (AZT), but not against HIV-2, simian immunodeficiency vir us or herpes simplex virus. An HIV-1 strain containing the 188 Tyr-->H is mutation in the reverse transcriptase displayed severely reduced se nsitivity to the compounds. The specificity of these compounds is due to an interaction with the reverse transcription process. The 6,7-dihy dro-7-methyl-12-ethyl-pyrido[2,3-b]pyrido [2,3-4,5]thieno[2,3-f][1,4]d iazepin-6(12H)-thione (MEN 10979) enhanced the anti-HIV-1. activity of AZT and dideoxyinosine (ddI) in a synergistic manner. The new arylpyr ido-diazepine and -thiodiazepine derivatives appear to be drug candida tes for the treatment of HIV-1 infection.