Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)

Christopher W West; Marc Adler; Danny Arnaiz; Deborah Chen; Kieu Chu; Giovanna Gualtieri; Elena Ho; Christoph Huwe; David Light; Gary Phillips; Rebecca Pulk; Drew Sukovich; Marc Whitlow; Shendong Yuan; Judi Bryant

doi:10.1016/j.bmcl.2009.08.008

Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)

Bioorg Med Chem Lett. 2009 Oct 1;19(19):5712-5. doi: 10.1016/j.bmcl.2009.08.008. Epub 2009 Aug 7.

Authors

Christopher W West¹, Marc Adler, Danny Arnaiz, Deborah Chen, Kieu Chu, Giovanna Gualtieri, Elena Ho, Christoph Huwe, David Light, Gary Phillips, Rebecca Pulk, Drew Sukovich, Marc Whitlow, Shendong Yuan, Judi Bryant

Affiliation

¹ Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. cwest@icagen.com

PMID: 19703768
DOI: 10.1016/j.bmcl.2009.08.008

Abstract

In this Letter we report the synthesis and evaluation of a series of non-amidine inhibitors of Urokinase Plasminogen Activator (uPA). Starting from compound 1, a significant change provided compounds in which the amidine, binding in the S1 pocket, was replaced with a primary amine. Further modifications led to the identification of potent, selective, and orally bioavailable uPA inhibitors.

MeSH terms

Administration, Oral
Amidines / chemistry
Animals
Benzylamines / chemistry*
Binding Sites
Crystallography, X-Ray
Humans
Rats
Serine Proteinase Inhibitors / administration & dosage
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / chemistry*
Structure-Activity Relationship
Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
Urokinase-Type Plasminogen Activator / metabolism

Substances

Amidines
Benzylamines
Serine Proteinase Inhibitors
benzylamine
Urokinase-Type Plasminogen Activator