Display Settings:

Format

Send to:

Choose Destination
ACS Med Chem Lett. 2012 Mar 8;3(3):232-237. Epub 2012 Jan 30.

Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor.

Abstract

A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure-activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile.

PMID:
22408714
[PubMed]
PMCID:
PMC3297361
Free PMC Article

Images from this publication.See all images (3)Free text

Scheme 1
Scheme 2
Figure 1
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for American Chemical Society Icon for PubMed Central
    Loading ...
    Write to the Help Desk