Delving into the Latest Updates on TM5007 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PAI-1

Mechanism

PAI-1 inhibitors(Plasminogen activator inhibitor 1 inhibitors)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Thrombosis

Inactive Indication-

Originator Organization

Tohoku University

Active Organization

Tohoku University

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC24H20N2O6S4

InChIKeyUSLUSWIVVBUXLU-UHFFFAOYSA-N

CAS Registry342595-05-5

Objective— Serine protease inhibitors (serpin) play a central role in various pathological processes including coagulation, fibrinolysis, malignancy, and inflammation. Inhibition of serpins may prove therapeutic. As yet, however, only very few small molecule serpin inhibitors have been reported. For the first time, we apply a new approach of virtual screening to discover novel, orally active, small molecule serpin inhibitors and report their effectiveness. Methods and Results— We focused on a clinically important serpin, plasminogen activator inhibitor-1 (PAI-1), whose crystal structure has been described. We identify novel, orally active molecules able to enter into the strand 4 position (s4A) of the A β-sheet of PAI-I as a mock compound. In vitro they specifically inhibit the PAI-1 activity and enhance fibrinolysis activity. In vivo the most effective molecule (TM5007) inhibits coagulation in 2 models: a rat arteriovenous (AV) shunt model and a mouse model of ferric chloride–induced testicular artery thrombosis. It also prevents the fibrotic process initiated by bleomycin in mouse lung. Conclusions— The present study demonstrates beneficial in vitro and in vivo effects of novel PAI-1 inhibitors. Our methodology proves to be a useful tool to obtain effective inhibitors of serpin activity.

100 Deals associated with TM5007

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