Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.
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.
Frederickson
Martyn
M
Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. m.frederickson@astex-therapeutics.com
Callaghan
Owen
O
Chessari
Gianni
G
Congreve
Miles
M
Cowan
Suzanna R
SR
Matthews
Julia E
JE
McMenamin
Rachel
R
Smith
Donna-Michelle
DM
Vinković
Mladen
M
Wallis
Nicola G
NG
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
D008801:Mexiletine; D014568:Urokinase-Type Plasminogen Activator