Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan; Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan.
Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan.
Bioorg Med Chem Lett. 2014 Jan 15;24(2):565-70. doi: 10.1016/j.bmcl.2013.12.020. Epub 2013 Dec 10.
We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30 mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases.
我们鉴定出基于 1-氧杂-4,9-二氮杂螺[5.5]十一烷的三取代脲是具有高活性的可溶性环氧化物水解酶（sEH）抑制剂和治疗慢性肾脏疾病的口服有效药物。化合物 19 表现出极好的 sEH 抑制活性和生物利用度。在抗肾小球基底膜肾小球肾炎大鼠模型中，19 以 30mg/kg 的剂量口服给药时可降低血清肌酐，但基于 2,8-二氮杂螺[4.5]癸烷的三取代脲则没有。这些结果表明，19 是一种用于治疗慢性肾脏疾病的口服活性药物候选物。
