title: Discovery and safety profiling of a potent preclinical candidate, (4-[4-[[(3R)-3-(hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the prevention and treatment of hemorrhage.
abstract: Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30 000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding.
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Josune
authors: J
authors: Orbe
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: José A
authors: JA
authors: Rodríguez
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Juan A
authors: JA
authors: Sánchez-Arias
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Agustina
authors: A
authors: Salicio
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Miriam
authors: M
authors: Belzunce
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Ana
authors: A
authors: Ugarte
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Haisul C Y
authors: HC
authors: Chang
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Obdulia
authors: O
authors: Rabal
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: Julen
authors: J
authors: Oyarzabal
authors: †Atherosclerosis Research Laboratory, ‡Small Molecule Discovery Platform, Molecular Therapeutics Program, §Experimental Hepathology, Center for Applied Medical Research (CIMA), and ∥Hematology Service, Clínica Universidad de Navarra, University of Navarra, Pamplona, 31008, Spain.
authors: José A
authors: JA
authors: Páramo
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006470:Hemorrhage / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D006490:Hemostatics / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods
chemical_list: C000598576:4-(4-((3-(hydroxycarbamoyl)-8-azaspiro(4.5)decan-3-yl)sulfonyl)phenoxy)-N-methylbenzamide; D000933:Antifibrinolytic Agents; D001549:Benzamides; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006490:Hemostatics; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10