P230Metalloproteinases inhibition: a new approach to reduce hemorrhage and blood transfusions

Abstract

Purpose: Bleeding can be a complication of surgery (e.g. cardiac surgery) leading to blood transfusion requirements and substantial morbidity and mortality having a great health and econimical impact. Hyperfibrinolysis is an integral component of bleeding in this condition, therefore administration of antifibrinolytics like tranexamic acid (TXA), is the strategy of choice. However, side effects associated with venous or arterial thrombosis and seizures, limit its use. We hypothesized that inhibition of metalloproteinases (MMPs) may represent a new therapeutic approach to control bleeding, based on its role on hemostasis. Methods: Through the implemented drug discovery process, based on in-vitro MMPs activity biochemical test and a functional thromboelastometry assay, synthesized compounds from a novel chemical series were prioritized to be assayed in-vivo. In particular , the compounds that show a 50 % significant delay in blood lysis time were tested in a tail bleeding model in mouse, and after partial hepatectomy as compared with TXA. Moreover, pathological studies were performed with a dose 10 times higher than the effective in ensuring the safety of the compound and discard thrombotic events. Finally the pharmacokinetics and toxicity of selected candidate was further analyzed. Results: After some iterations a lead compound was achieved: CM-352 significantly reduced the bleeding time by 89% in the hyperfibrinolytic tail bleeding model at a dose of 10 ug/Kg - 30,000 times lower than TXA. Moreover, CM-352 was also effective at reducing blood loss after liver laceration, where TXA had no significant effect. CM-352 showed optimal ADME/Tox and pharmacokinetic profile as well as cardiovascular safety; in addition, anatomopathological analysis (at 10 mg/kg) showed no thrombus formation in lung, brain, kidney or liver. Conclusions:Ourfindings demonstrate that CM-352inhibits fibrinolysis and reduces blood loss safely and efficiently through anewmechanism of action, which underscores its potential for patients suffering major bleeding due to various medical and surgical conditions.