Yonesu Kiyoaki, Kawase Yumi, Inoue Tatsuya, Takagi Nana, Tsuchida Jun, Takuwa Yoh, Kumakura Seiichiro, Nara Futoshi
Exploratory Research Laboratories II, Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Biochem Pharmacol. 2009 Mar 15;77(6):1011-20. doi: 10.1016/j.bcp.2008.12.007. Epub 2008 Dec 27.
Chemical lead 2 (CL2) is the first non-sphingosine-1-phosphate (Sph-1-P) analog type antagonist of endothelial differentiation gene-1 (Edg-1/S1P(1)), which is a member of the Sph-1-P receptor family. CL2 inhibits [(3)H]Sph-1-P/S1P(1) binding and shows concentration-dependent inhibition activity against both intracellular cAMP concentration decrease and cell invasion induced by the Sph-1-P/S1P(1) pathway. It also inhibits normal tube formation in an angiogenesis culture model, indicating that CL2 has anti-angiogenesis activity. This compound improved the disease conditions in two angiogenic models in vivo. It significantly inhibited angiogenesis induced by vascular endothelial growth factor in a rabbit cornea model as well as the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. These results indicate that the Sph-1-P/S1P(1) pathway would have an important role in disease-related angiogenesis, especially in the processes of migration/invasion and tube formation. In addition, CL2 would be a powerful tool for the pharmacological study of the mechanisms of the Sph-1-P/S1P(1) pathway in rheumatoid arthritis, diabetes retinopathy, and solid tumor growth processes.
化学铅2（CL2）是内皮分化基因-1（Edg-1/S1P(1)）的首个非鞘氨醇-1-磷酸（Sph-1-P）类似物类型拮抗剂，Edg-1/S1P(1)是Sph-1-P受体家族的成员。CL2抑制[(3)H]Sph-1-P/S1P(1)结合，并对Sph-1-P/S1P(1)途径诱导的细胞内cAMP浓度降低和细胞侵袭均表现出浓度依赖性抑制活性。它还在血管生成培养模型中抑制正常的血管生成，表明CL2具有抗血管生成活性。该化合物在两种体内血管生成模型中改善了疾病状况。它在兔角膜模型中显著抑制血管内皮生长因子诱导的血管生成，以及在抗II型胶原抗体诱导的关节炎模型中抑制小鼠足部肿胀。这些结果表明，Sph-1-P/S1P(1)途径在疾病相关的血管生成中，尤其是在迁移/侵袭和血管生成过程中具有重要作用。此外，CL2将成为类风湿性关节炎、糖尿病视网膜病变和实体瘤生长过程中Sph-1-P/S1P(1)途径机制药理学研究的有力工具。
