Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, United States.
Bioorg Med Chem Lett. 2010 Jan 15;20(2):571-5. doi: 10.1016/j.bmcl.2009.11.091. Epub 2009 Nov 22.
Inhibition of sEH is hypothesized to lead to an increase in epoxyeicosatrienoic acids resulting in the potentiation of their anti-inflammatory and vasodilatory effects. In an effort to explore sEH inhibition as an avenue for the development of vasodilatory and cardio- or renal-protective agents, a lead identified through high-throughput screening was optimized, guided by the determination of a solid state co-structure with sEH. Replacement of potential toxicophores was followed by optimization of cell-based potency and ADME properties to provide a new class of functionally potent sEH inhibitors with attractive in vitro metabolic profiles and high and sustained plasma exposures after oral administration in the rat.
抑制 sEH 被假设会导致环氧二十碳三烯酸的增加，从而增强其抗炎和血管舒张作用。为了探索 sEH 抑制作为开发血管舒张和心脏或肾脏保护剂的途径，通过高通量筛选确定了一个先导化合物，并通过与 sEH 的确定固态共结构进行了优化。在优化基于细胞的效力和 ADME 特性的同时，替换潜在的毒性部分，以提供一类新的具有功能效力的 sEH 抑制剂，具有有吸引力的体外代谢特征和在大鼠口服给药后的高和持续的血浆暴露。
