Unknown

Dataset Information

0

Discovery of the Fibrinolysis Inhibitor AZD6564, Acting via Interference of a Protein-Protein Interaction.

ABSTRACT: A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6564 (19) displaying an in vitro human plasma clot lysis IC50 of 0.44 ?M, no detectable activity against GABAa, and with DMPK properties leading to a predicted dose of 340 mg twice a day oral dosing in humans.

SUBMITTER: Cheng L 

PROVIDER: S-EPMC4027757 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

A class of novel oral fibrinolysis inhibitors has been discovered, which are lysine mimetics containing an isoxazolone as a carboxylic acid isostere. As evidenced by X-ray crystallography the inhibitors bind to the lysine binding site in plasmin thus preventing plasmin from binding to fibrin, hence blocking the protein-protein interaction. Optimization of the series, focusing on potency in human buffer and plasma clotlysis assays, permeability, and GABAa selectivity, led to the discovery of AZD6  ...[more]

Similar Datasets

Unknown Query-guided protein-protein interaction inhibitor discovery.
| S-EPMC8179539 | biostudies-literature
Unknown Activated platelet-based inhibition of fibrinolysis via thrombin-activatable fibrinolysis inhibitor activation system.
| S-EPMC7656914 | biostudies-literature
Unknown Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction.
| S-EPMC3648997 | biostudies-literature
Unknown Discovery and structural characterization of a small molecule 14-3-3 protein-protein interaction inhibitor.
| S-EPMC3182712 | biostudies-literature
Unknown AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
| S-EPMC10987651 | biostudies-literature
Unknown AI-guided pipeline for protein-protein interaction drug discovery identifies a SARS-CoV-2 inhibitor.
| S-EPMC10312674 | biostudies-literature
Unknown Inhibitor-3 inhibits Protein Phosphatase 1 via a metal binding dynamic protein-protein interaction.
| S-EPMC10066265 | biostudies-literature
Unknown Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.
| S-EPMC8817233 | biostudies-literature
Unknown Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates.
| S-EPMC2992258 | biostudies-literature
Unknown Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.
| S-EPMC3728914 | biostudies-literature