Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs

Article abstract of DOI:10.1021/jm00025a010

A novel series of potent specific HIV-1 inhibitory compounds is described. 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 IC₅₀ of 0.9 μM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED₅₀ of 1.3 μM. The 50% cytotoxic dose in cell culture is >380 μM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2- pyridyl)-thiourea (62; LY300046 · HCl) as a candidate for clinical evaluation. LY300046 · HCl inhibits HIV-1 RT with an IC₅₀ of 15 nM and in cell culture has an ED₅₀ of 20 nM.