Hategan Georgeta, Polozov Alexandre M, Zeller Wayne, Cao Hua, Mishra Rama K, Kiselyov Alex S, Ramirez Jose, Halldorsdottir Gudrún, Andrésson Thornorkell, Gurney Mark E, Singh Jasbir
Medicinal Chemistry Department, deCODE Chemistry, Inc, Woodridge, IL 60517, United States.
Bioorg Med Chem Lett. 2009 Dec 1;19(23):6797-800. doi: 10.1016/j.bmcl.2009.09.084. Epub 2009 Sep 27.
We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.
我们基于前列腺素E2（PGE2）这一内源性配体，开发了一种前列腺素E3（EP(3)）受体拮抗剂的药效团模型。这种基于配体的设计产生了一系列新型的周边取代的[4.3.0]双环芳烃，其特征为1-烷基芳基7-杂环磺酰胺取代基。合成的分子在体外是人类EP(3)受体的强效拮抗剂，并显示出对大鼠血小板聚集的抑制作用。优化后的衍生物对IP、FP和其他EP受体亚型表现出高选择性。
