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: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 7 Pg. 2941-57 (Apr 09 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25686022 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Antifibrinolytic Agents (chemistry, pharmacology)
• Benzamides (chemistry, 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, metabolism, prevention & control)
• Hemostatics (chemistry, pharmacology)
• Humans
• Hydroxamic Acids (chemistry, pharmacology)
• Matrix Metalloproteinase 10 (metabolism)
• Matrix Metalloproteinase 3 (metabolism)
• Matrix Metalloproteinase Inhibitors (chemistry, pharmacology)
• Mice, Inbred C57BL
• Molecular Structure
• Molecular Targeted Therapy (methods)