title: Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.
abstract: Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.
authors.affiliation: Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. m.frederickson@astex-therapeutics.com
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Owen
authors.initials: O
authors.lastname: Callaghan
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: Suzanna R
authors.initials: SR
authors.lastname: Cowan
authors.forename: Julia E
authors.initials: JE
authors.lastname: Matthews
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.forename: Donna-Michelle
authors.initials: DM
authors.lastname: Smith
authors.forename: Mladen
authors.initials: M
authors.lastname: Vinković
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D008801:Mexiletine; D014568:Urokinase-Type Plasminogen Activator