抗纤维溶解
药理学
计算生物学
医学
氨甲环酸
生物
外科
失血
作者
Irene de Miguel,Josune Orbe,Juan A. Sánchez‐Arias,José Antonio Rodríguez,Agustina Salicio,Obdulia Rabal,M. Belzunce,Elena Sáez,Min Xu,Wei Wu,Tan Haizhong,Hongyu Ma,José A. Páramo,Julen Oyarzábal
标识
DOI:10.1021/acsmedchemlett.7b00549
摘要
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 38 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 39 was successfully designed to identify the target involved in this response: a potentially unknown mechanism-of-action in the fibrinolytic process.
科研通智能强力驱动
Strongly Powered by AbleSci AI