Phenotypic Screening To Discover Novel Chemical Series as Efficient Antihemorrhagic Agents
Irene de Miguel, Josune Orbe, Juan A. Sánchez-Arias, José A. Rodríguez, Agustina Salicio, Obdulia Rabal, Miriam Belzunce, Elena Sáez, Musheng Xu, Wei Wu, Haizhong Tan, Hongyu Ma, José A. Páramo, and Julen Oyarzabal
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.
CITA DEL ARTÍCULO ACS Med. Chem. Lett. 2018, 9, 5, 428–433 https://doi.org/10.1021/acsmedchemlett.7b00549