de Miguel Irene, Orbe Josune, Sánchez-Arias Juan A, Rodríguez José A, Salicio Agustina, Rabal Obdulia, Belzunce Miriam, Sáez Elena, Xu Musheng, Wu Wei, Tan Haizhong, Ma Hongyu, Páramo José A, Oyarzabal Julen
Small Molecule Discovery Platform, Molecular Therapeutics Program, and Atherothrombosis Research Laboratory, Program of Cardiovascular Diseases, Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain.
CIBER Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.
ACS Med Chem Lett. 2018 Apr 16;9(5):428-433. doi: 10.1021/acsmedchemlett.7b00549. eCollection 2018 May 10.
In an effort to find novel chemical series as antifibrinolytic agents, we explore α-phenylsulfonyl-α-spiropiperidines bearing different zinc-binding groups (ZBGs) to target those metalloproteinases involved in the fibrinolytic process: MMP3 and MMP10. Surprisingly, all these new chemical series were inactive against these metalloproteinases; however, several new molecules retained the antifibrinolytic activity in a phenotypic functional assay using thromboelastometry and human whole blood. Further optimization led to compound as a potent antifibrinolytic agent in vivo, three times more efficacious than the current standard-of-care (tranexamic acid, TXA) at 300 times lower dose. Finally, in order to decipher the underlying mode-of-action leading to this phenotypic response, an affinity-based probe was successfully designed to identify the target involved in this response: a potentially unknown mechanism-of-action in the fibrinolytic process.
为了寻找新型化学系列作为抗纤溶药物，我们探索了带有不同锌结合基团（ZBG）的α-苯磺酰基-α-螺哌啶，以靶向参与纤溶过程的金属蛋白酶：MMP3和MMP10。令人惊讶的是，所有这些新化学系列对这些金属蛋白酶均无活性；然而，在使用血栓弹力图和人全血的表型功能试验中，几种新分子保留了抗纤溶活性。进一步优化得到了化合物，它在体内是一种有效的抗纤溶药物，在剂量低300倍时比当前的护理标准（氨甲环酸，TXA）有效三倍。最后，为了解释导致这种表型反应的潜在作用模式，成功设计了一种基于亲和力的探针，以鉴定参与这种反应的靶点：纤溶过程中一种潜在未知的作用机制。
