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ID: ALA4145591
Journal: ACS Med Chem Lett
Title: Phenotypic Screening To Discover Novel Chemical Series as Efficient Antihemorrhagic Agents.
Authors: de Miguel I, Orbe J, Sánchez-Arias JA, Rodríguez JA, Salicio A, Rabal O, Belzunce M, Sáez E, Xu M, Wu W, Tan H, Ma H, Páramo JA, Oyarzabal J.
Abstract: 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.
CiteXplore: 29795754