Structure-activity relationships of new 2-acylamino-3-thiophenecarboxylic acid dimers as plasminogen activator inhibitor-1 inhibitors.
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).
Yamaoka
Nagahisa
N
CT Laboratory, Hamari Chemicals, Ltd., 1-4-29 Kunijima, Higashiyodogawa-ku, Osaka 533-0024, Japan. nagahisa-yamaoka@hamari.co.jp
Kawano
Yasuhiko
Y
Izuhara
Yuko
Y
Miyata
Toshio
T
Meguro
Kanji
K
D000215:Acylation; D000588:Amines / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019281:Dimerization; D006801:Humans; D015394:Molecular Structure; D017395:Plasminogen Activator Inhibitor 1 / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
D000588:Amines; D002264:Carboxylic Acids; D017395:Plasminogen Activator Inhibitor 1; D013876:Thiophenes