Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines.
A series of 1-isoquinolinylguanidines are shown to be potent inhibitors of uPA with selectivity over tPA and plasmin. Potency is enhanced by the presence of a 4-halo and a 7-aryl substituent, particularly when substituted by a 3-carboxylic acid group. Compound 13j (UK-356,202) combines excellent potency and selectivity, and has been selected as a candidate for clinical evaluation.
Barber
Christopher G
CG
Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. christopher_barber@sandwich.pfizer.com
Dickinson
Roger P
RP
Fish
Paul V
PV
D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D011237:Predictive Value of Tests; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
D006146:Guanidines; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors; D014568:Urokinase-Type Plasminogen Activator