Synthesis and SAR of 2-carboxylic acid indoles as inhibitors of plasminogen activator inhibitor-1.

We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.

WAY-140312 reduces plasma PAI-1 while maintaining normal platelet aggregation.

Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of tissue plasminogen activator (tPA) and is elevated in diseases of vascular remodeling. In this study, we describe an inhibitor of active PAI-1, WAY-140312. Using fluorescence spectroscopy, it was determined that WAY-140312 bound PAI-1 at a single binding site with a dissociation constant of 5 microM. In a biochemical assay determining direct tPA activity, human recombinant PAI-1 completely inhibited tPA, but this inhibition was blocked by WAY-140312 at an IC(50) of 15.6 microM. In vivo, a 10 mg/kg oral dose of WAY-140312 to rats produced a significant plasma reduction of active PAI-1. Bleeding time, thrombin clotting time, and ex vivo platelet aggregation induced by ADP (20 microM) or collagen (2.5 microg/ml) were not affected by administration of WAY-140312. These results are the first to demonstrate that an orally active PAI-1 inhibitor can reduce plasma PAI-1 activity while maintaining normal platelet aggregation and coagulation.