PHENETHYLTHIAZOLETHIOUREA (PETT) COMPOUNDS, A NEW CLASS OF HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS .1. SYNTHESIS AND BASIC STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF PETT ANALOGS

A novel series of potent specific HIV-1 inhibitory compounds is descri bed. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl) thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC5 0 of 0.9 mu M. In MT-4 cells, compound 1 inhibits HIV-1 with an ED(50) of 1.3 mu M. The 50% cytotoxic dose in cell culture is >380 mu M. The chemical structure-activity relationship (SAR) was developed by notio nally dividing the lead compound in four quadrants. The SAR strategy h ad two phases. The first phase involved optimization of antiviral acti vity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of th ese substituents. Further SAR studies and pharmacokinetic consideratio ns led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)th iourea (62; LY300046 . HCl) as a candidate for clinical evaluation. LY 300046 . HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell cultu re has an ED(50) of 20 nM.