Scientific publications

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

Apr 1, 2015 | Magazine: Journal of Medicinal Chemistry

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).


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.

Our authors

Dr. Josune Orbe Lopategui
Dr. José Antonio Rodríguez García
Agustina Salicio Castillo
Laboratory technician Atherothrombosis Research Group
Miriam Belzunce Saldise