Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines

Christopher G Barber; Roger P Dickinson; Paul V Fish

doi:10.1016/j.bmcl.2004.03.094

Selective urokinase-type plasminogen activator (uPA) inhibitors. Part 3: 1-isoquinolinylguanidines

Bioorg Med Chem Lett. 2004 Jun 21;14(12):3227-30. doi: 10.1016/j.bmcl.2004.03.094.

Authors

Christopher G Barber¹, Roger P Dickinson, Paul V Fish

Affiliation

¹ Department of Discovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. christopher_barber@sandwich.pfizer.com

PMID: 15149680
DOI: 10.1016/j.bmcl.2004.03.094

Abstract

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.

MeSH terms

Guanidines / chemistry*
Guanidines / pharmacology
Humans
Isoquinolines / chemistry*
Isoquinolines / pharmacology
Predictive Value of Tests
Serine Proteinase Inhibitors / chemistry*
Serine Proteinase Inhibitors / pharmacology
Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
Urokinase-Type Plasminogen Activator / metabolism

Substances

Guanidines
Isoquinolines
Serine Proteinase Inhibitors
Urokinase-Type Plasminogen Activator