Emory Institute for Drug Discovery, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
J Med Chem. 2012 May 10;55(9):4220-30. doi: 10.1021/jm201699w. Epub 2012 Apr 20.
The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase by means of high-throughput screening. Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC(50) = 60 nM) with an aqueous solubility of approximately 60 μg/mL. The agent shows a 10-fold exposure (AUC/C(max)) increase in the rat model relative to 2, displays near dose proportionality in the range of 10-50 mg/kg, and exhibits good oral bioavailability (F = 39%). The significant solubility increase appears linked to the improved oral bioavailability.
麻疹病毒（MeV）是副粘病毒科的一员，是全球导致儿童发病和死亡的重要原因。为了寻找治疗方法来改善麻疹的管理，我们之前通过高通量筛选发现了一种针对病毒 RNA 依赖性 RNA 聚合酶的小型非核苷有机抑制剂。随后围绕相应的吡唑甲酰胺支架进行的构效关系（SAR）研究发现了 2（AS-136a），这是一种具有低纳摩尔效力的第一代先导化合物，对生命 MeV 具有吸引力，并且具有适合开发的物理特性。然而，其在大鼠中的低水溶性和低口服生物利用度（F）表明，该先导化合物可能受益于进一步的 SAR 研究，以改善化合物的生物物理特性。对体外效力和水溶解度的优化导致发现了 2o（ERDRP-00519），这是一种有效的 MeV 抑制剂（EC50=60 nM），水溶解度约为 60 μg/mL。与 2 相比，该药物在大鼠模型中的暴露量（AUC/C(max)）增加了 10 倍，在 10-50 mg/kg 范围内接近剂量比例，并且具有良好的口服生物利用度（F=39%）。显著提高的溶解度似乎与改善的口服生物利用度有关。
