NOVEL NONNUCLEOSIDE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1(HIV-1) REVERSE-TRANSCRIPTASE .4. 2-SUBSTITUTED DIPYRIDODIAZEPINONES AS POTENT INHIBITORS OF BOTH WILD-TYPE AND CYSTEINE-181 HIV-1 REVERSE-TRANSCRIPTASE ENZYMES

The major cause of viral resistance to the potent human immunodeficien cy virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT), An evaluation, against Y181C RT, of previously described analogs of nevir apine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the stru cture-activity relationship of 2-substituted dipyridodiazepinones pres ented below shows that combined activity against the wildtype and Y181 C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N -5, and N-11 of the dipyridodiazepinone ring system optimum for inhibi tion of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclo propyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 8-s ubstituted dipyridodiazepinones were evaluated against mutant RT enzym es (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectivel y, at the 2-position, were found to be effective inhibitors of these m utant enzymes also.