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

Josune Orbe; José A Rodríguez; Juan A Sánchez-Arias; Agustina Salicio; Miriam Belzunce; Ana Ugarte; Haisul C Y Chang; Obdulia Rabal; Julen Oyarzabal; José A Páramo

doi:10.1021/jm501939z

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

J Med Chem. 2015 Apr 9;58(7):2941-57. doi: 10.1021/jm501939z. Epub 2015 Feb 25.

Affiliation

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.

PMID: 25686022
DOI: 10.1021/jm501939z

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antifibrinolytic Agents / chemistry
Antifibrinolytic Agents / pharmacology
Benzamides / chemistry
Benzamides / pharmacology*
Caco-2 Cells / drug effects
Drug Discovery / methods
Drug Evaluation, Preclinical / methods*
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
Hemorrhage / drug therapy
Hemorrhage / metabolism
Hemorrhage / prevention & control*
Hemostatics / chemistry*
Hemostatics / pharmacology*
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Matrix Metalloproteinase 10 / metabolism
Matrix Metalloproteinase 3 / metabolism
Matrix Metalloproteinase Inhibitors / chemistry
Matrix Metalloproteinase Inhibitors / pharmacology
Mice, Inbred C57BL
Molecular Structure
Molecular Targeted Therapy / methods

Substances

4-(4-((3-(hydroxycarbamoyl)-8-azaspiro(4.5)decan-3-yl)sulfonyl)phenoxy)-N-methylbenzamide
Antifibrinolytic Agents
Benzamides
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Hemostatics
Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 3
Matrix Metalloproteinase 10