新型S1P2拮抗剂的发现。第2部分：改善一系列1,3-双（芳氧基）苯衍生物的特性。
Discovery of novel S1P2 antagonists. Part 2: Improving the profile of a series of 1,3-bis(aryloxy)benzene derivatives.
作者信息
Kusumi Kensuke, Shinozaki Koji, Yamaura Yoshiyuki, Hashimoto Ai, Kurata Haruto, Naganawa Atsushi, Ueda Hideyuki, Otsuki Kazuhiro, Matsushita Takeshi, Sekiguchi Tetsuya, Kakuuchi Akito, Seko Takuya
机构信息
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Ono Pharma UK Ltd, MidCity Place, 71 High Holborn, London WC1V 6EA, United Kingdom.
出版信息
Bioorg Med Chem Lett. 2015 Oct 15;25(20):4387-92. doi: 10.1016/j.bmcl.2015.09.022. Epub 2015 Sep 8.
Our initial lead compound 2 was modified to improve its metabolic stability. The resulting compound 5 showed excellent metabolic stability in rat and human liver microsomes. We subsequently designed and synthesized a hybrid compound of 5 and the 1,3-bis(aryloxy) benzene derivative 1, which was previously reported by our group to be an S1P2 antagonist. This hybridization reaction gave compound 9, which showed improved S1P2 antagonist activity and good metabolic stability. The subsequent introduction of a carboxylic acid moiety into 9 resulted in 14, which showed potent antagonist activity towards S1P2 with a much smaller species difference between human S1P2 and rat S1P2. Compound 14 also showed good metabolic stability and an improved safety profile compared with compound 9.
我们对最初的先导化合物2进行了修饰，以提高其代谢稳定性。所得化合物5在大鼠和人肝微粒体中显示出优异的代谢稳定性。随后，我们设计并合成了化合物5与1,3-双（芳氧基）苯衍生物1的杂化化合物，我们小组之前报道该衍生物为S1P2拮抗剂。这种杂交反应得到了化合物9，其显示出改善的S1P2拮抗剂活性和良好的代谢稳定性。随后在9中引入羧酸部分得到了化合物14，其对S1P2显示出强效拮抗剂活性，且人S1P2和大鼠S1P2之间的种属差异小得多。与化合物9相比，化合物14还显示出良好的代谢稳定性和改善的安全性。
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