Synthia LLC, Davis, CA 95616, United States.
Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States.
Bioorg Med Chem. 2020 Nov 15;28(22):115735. doi: 10.1016/j.bmc.2020.115735. Epub 2020 Aug 31.
Soluble epoxide hydrolase (sEH), a novel therapeutic target for neuropathic pain, is a largely cytosolic enzyme that degrades epoxy-fatty acids (EpFAs), an important class of lipid signaling molecules. Many inhibitors of sEH have been reported, and to date, the 1,3-disubstituted urea has the highest affinity reported for the sEH among the central pharmacophores evaluated. An earlier somewhat water soluble sEH inhibitor taken to the clinic for blood pressure control had mediocre potency (both affinity and kinetics) and a short in vivo half-life. We undertook a study to overcome these difficulties, but the sEH inhibitors carrying a 1,3-disubstituted urea often suffer poor physical properties that hinder their formulation. In this report, we described new strategies to improve the physical properties of sEH inhibitors with a 1,3-disubstituted urea while maintaining their potency and drug-target residence time (a complementary in vitro parameter) against sEH. To our surprise, we identified two structural modifications that substantially improve the potency and physical properties of sEH inhibitors carrying a 1,3-disubstituted urea pharmacophore. Such improvements will greatly facilitate the movement of sEH inhibitors to the clinic.
可溶性环氧化物水解酶（sEH）是一种新型的治疗神经性疼痛的靶点，它是一种主要存在于细胞质中的酶，可以降解环氧脂肪酸（EpFAs），这是一类重要的脂质信号分子。已经报道了许多 sEH 的抑制剂，到目前为止，在所评估的中枢药效团中，1,3-取代脲对 sEH 的亲和力最高。一种早期用于控制血压的水溶性稍好的 sEH 抑制剂，其效力（亲和力和动力学）都一般，体内半衰期也较短。我们开展了一项研究来克服这些困难，但带有 1,3-取代脲的 sEH 抑制剂通常具有较差的物理性质，这阻碍了它们的制剂开发。在本报告中，我们描述了新的策略，以改善带有 1,3-取代脲药效团的 sEH 抑制剂的物理性质，同时保持其对 sEH 的效力和药物靶点停留时间（互补的体外参数）。令我们惊讶的是，我们确定了两种结构修饰，它们可以大大提高带有 1,3-取代脲药效团的 sEH 抑制剂的效力和物理性质。这些改进将极大地促进 sEH 抑制剂进入临床。
