ABSTRACT
Small molecule inhibitors of plasminogen activator inhibitor (PAI)-1 have been reported to date but their clinical effects still remain unknown. The present study was undertaken to investigate the structure-activity relationships (SAR) of newly synthesized 2-acylamino-3-thiophenecarboxylic acid dimers based upon a core structure of TM5001 (1) and TM5007 (2) that we have previously identified as orally effective PAI-1 inhibitors. In general, compounds possessing bulky or/and hydrophobic substituents (e.g. phenyl, isobutyl group) on the both thiophene rings showed potent PAI-1 inhibitory activities irrespective of the positions of the substitution. The mono-carboxyl derivative (10) exhibited PAI-1 inhibition comparable to the corresponding dicarboxyl compound (9f).
Subject(s)
Amines/chemistry , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Plasminogen Activator Inhibitor 1/chemistry , Plasminogen Activator Inhibitor 1/pharmacology , Thiophenes/chemistry , Acylation , Carboxylic Acids/chemical synthesis , Dimerization , Humans , Molecular Structure , Plasminogen Activator Inhibitor 1/chemical synthesis , Structure-Activity RelationshipABSTRACT
We have synthesized and evaluated a series of tetramic acid-based and hydroxyquinolinone-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). These studies resulted in the identification of several compounds which showed excellent potency against PAI-1. The design, synthesis and SAR of these compounds are described.
