RGD Reference Report - Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis. - Rat Genome Database

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Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis.

Authors: Izuhara, Y  Takahashi, S  Nangaku, M  Takizawa, S  Ishida, H  Kurokawa, K  Van Ypersele de Strihou, C  Hirayama, N  Miyata, T 
Citation: Izuhara Y, etal., Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):672-7. Epub 2008 Jan 31.
RGD ID: 2316121
Pubmed: PMID:18239154   (View Abstract at PubMed)
DOI: DOI:10.1161/ATVBAHA.107.157479   (Journal Full-text)

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 beta-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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of coagulation  IMP 2316121 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Serpine1  (serpin family E member 1)


Additional Information