Bell F W, Cantrell A S, Högberg M, Jaskunas S R, Johansson N G, Jordan C L, Kinnick M D, Lind P, Morin J M, Noréen R
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
J Med Chem. 1995 Dec 8;38(25):4929-36. 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 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. 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.
描述了一系列新型强效特异性HIV-1抑制化合物。该系列中的先导化合物N-(2-苯乙基)-N'-(2-噻唑基)硫脲(1)，以rCdG为模板抑制HIV-1逆转录酶，IC50为0.9微摩尔。在MT-4细胞中，化合物1抑制HIV-1的ED50为1.3微摩尔。细胞培养中的50%细胞毒性剂量>380微摩尔。通过将先导化合物概念性地划分为四个象限来建立化学结构-活性关系(SAR)。SAR策略有两个阶段。第一阶段涉及通过独立改变象限1-4来优化抗病毒活性。第二阶段涉及制备结合这些最佳取代基的杂合结构。进一步的SAR研究和药代动力学考虑导致确定N-(2-吡啶基)-N'-(5-溴-2-吡啶基)-硫脲(62；LY300046.HCl)作为临床评估的候选药物。LY300046.HCl抑制HIV-1逆转录酶的IC50为15纳摩尔，在细胞培养中的ED50为20纳摩尔。
