title: Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA).
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.
authors.affiliation: Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. cwest@icagen.com
authors.forename: Christopher W
authors.initials: CW
authors.lastname: West
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Danny
authors.initials: D
authors.lastname: Arnaiz
authors.forename: Deborah
authors.initials: D
authors.lastname: Chen
authors.forename: Kieu
authors.initials: K
authors.lastname: Chu
authors.forename: Giovanna
authors.initials: G
authors.lastname: Gualtieri
authors.forename: Elena
authors.initials: E
authors.lastname: Ho
authors.forename: Christoph
authors.initials: C
authors.lastname: Huwe
authors.forename: David
authors.initials: D
authors.lastname: Light
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pulk
authors.forename: Drew
authors.initials: D
authors.lastname: Sukovich
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry; D000818:Animals; D001596:Benzylamines / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000578:Amidines; D001596:Benzylamines; D015842:Serine Proteinase Inhibitors; C030796:benzylamine; D014568:Urokinase-Type Plasminogen Activator