PHENETHYLTHIAZOLYLTHIOUREA (PETT) COMPOUNDS AS A NEW CLASS OF HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS .2. SYNTHESIS AND FURTHER STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF PETT ANALOGS

Phenylethylthiazolylthiourea (PETT) derivatives have been identified a s a new series of nonnucleoside inhibitors of HIV-1 RT. Structure-acti vity relationship studies of this class of compounds resulted in the i dentification of -(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea hy drochloride (trovirdine; LY300046 . HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for poten tial use in the treatment of AIDS. Extension of these structure-activi ty relationship studies to identify additional compounds in this serie s with improved properties is ongoing. A part of this work is describe d here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was inve stigated. In addition, the effects of multiple substitution in the phe nyl ring were also studied. The antiviral activities were determined o n wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell cultur e assays. Some selected compounds were determined on double-mutant vir uses, HIV-1 (Ile100/Asn103) and HIV-1 (Ile100/Cys181). A number of hig hly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agen ts inhibited wild-type HIV-1 with ED(50)'s between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 1 00) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) wit h IC50's between 4 and 10 nM, and in cell culture they inhibited mutan t HIV-1 (Ile100) with ED(50)'s between 9 and 100 nM and mutant HIV-1 ( Cys181) with ED(50)'s between 3 and 20 nM.