Structure–Activity Relationships of New 2-Acylamino-3-thiophenecarboxylic Acid Dimers as Plasminogen Activator Inhibitor-1 Inhibitors

• Published in: Chemical & Pharmaceutical Bulletin Vol. 58; no. 5; pp. 615 - 619
• Main Authors: Yamaoka, Nagahisa, Kawano, Yasuhiko, Izuhara, Yuko, Miyata, Toshio, Meguro, Kanji
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.05.2010; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: Acylation; Amines - chemistry; aminothiophenecarboxylic acid derivative; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Dimerization; Humans; inhibitor; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Plasminogen Activator Inhibitor 1 - chemical synthesis; Plasminogen Activator Inhibitor 1 - chemistry; Plasminogen Activator Inhibitor 1 - pharmacology; plasminogen activator inhibitor-1; Science & Technology; Structure-Activity Relationship; Thiophenes - chemistry; tissue-type plasminogen activator; GEWALD REACTION; plasminogen activator inhibitor-1; inhibitor; MECHANISM; PAI-1; structure activity relationship; tissue-type plasminogen activator; aminothiophenecarboxylic acid derivative
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.58.615

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).