Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1788-92. doi: 10.1016/j.bmcl.2011.12.019. Epub 2012 Jan 2.
S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC(50) value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID(50) value was determined at 0.407mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100.
S1P(3)-选择性 S1P(1)激动剂因其副作用降低而被作为自身免疫抑制剂受到关注。我们的合成努力和广泛的 SAR 研究导致了 10b 的发现，其 EC(50)值为 4.0 nM，对人源 S1P(1)具有超过 5000 倍的选择性，对 S1P(3)具有超过 5000 倍的选择性。在大鼠的移植物抗宿主反应中评估了 CS-2100 的体内免疫抑制功效，并确定了 ID(50)值为 0.407mg/kg。CS-2100 与 S1P(1)和 S1P(3)同源模型的对接研究表明，CS-2100 噻吩环上的乙基基团在 S1P(3)中受到 Phe263 的空间位阻，而在 S1P(1)中则不受 Leu276 的空间位阻。这一观察结果解释了 CS-2100 优异的 S1P(3)-选择性特征。
