NOVEL NONNUCLEOSIDE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1REVERSE-TRANSCRIPTASE .5. 4-SUBSTITUTED AND 2,4-DISUBSTITUTED ANALOGSOF NEVIRAPINE

Molecular modeling analysis of the recently published X-ray crystal st ructure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-PT) indicated the presence of a lipop hilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to asses s structure-activity relationships (SARs) and to see if increased bind ing to this region might translate into greater activity against mutan t RTs. The results show that compounds with an appropriately spaced ar yl ring appended to the 4-position of the dipyridodiazepinone ring sys tem show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these resul ts with the recent discovery that 2-substituents enhance activity agai nst the Y181C mutant led to a few compounds with moderate activity aga inst both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.