Design, Synthesis, and Biological Evaluation of Non-Symmetric Small Molecules as Inhibitors of Plasminogen Activator Inhibitor (PAI-1).

摘要

Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin family of proteins, a primary inhibitor of both tissue-type and urokinase-type plasminogen activators in plasma, and is a well-established risk factor in various disease conditions. Increased levels of active PAI-1 in plasma are correlated with the development of atherosclerosis, diabetes, stroke, and other maladies. In the present study, we describe the synthesis of two new series of compounds that aim to reduce physiologically active PAI-1 levels. These molecules are related to a series of bis-arylsulfonimides and arylsulfonamides connected by short linking diamines, and to a series of hydrazine-based analogues. These studies resulted in the identification of small molecule inhibitors of PAI-1 that displayed in vitro IC50 values in the low micromolar range.