THE PETT SERIES, A NEW CLASS OF POTENT NONNUCLEOSIDE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE

To identify the minimal structural elements necessary for biological a ctivity, the rigid tricyclic nucleus of the known human immunodeficien cy virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydr oimidazobenzodiazepinthione was subjected to systematic bond disconnec tion to obtain simpler structures. A rational selection and testing of modeled analogs containing these potential pharmacophoric moieties le d to the discovery of a new series of nonnucleoside inhibitors of RT. The lead compound of this new PETT series of nonnucleoside RT inhibito rs, N-(2-phenylethyl)-N'-(2-thiazolyl)thiourea (LY73497), was found to inhibit HIV-1 but not HIV-2 or simian immunodeficiency virus in cell culture at micromolar concentrations. This derivative was also found t o inhibit HIV-1 RT. Through an integrated effort involving synthesis a nd molecular modeling, compounds with nanomolar potency against HIV-1 in cell culture were developed. In these studies, LY300046-HCl was ide ntified as a potent nonnucleoside inhibitor of HIV-1 RT possessing fav orable pharmacokinetic properties.