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
Orbe J(1), Rodríguez JA(1), Sánchez-Arias JA(1), Salicio A(1), Belzunce M(1), Ugarte A(1), Chang HC(1), Rabal O(1), Oyarzabal J(1), Páramo JA(1).
(1) 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.
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.
CITATION J Med Chem. 2015 Apr 9;58(7):2941-57. doi: 10.1021/jm501939z.