 |
PDBsum entry 2viv
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Fragment-Based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-Type plasminogen activator.
|
|
|
Authors
|
|
M.Frederickson,
O.Callaghan,
G.Chessari,
M.Congreve,
S.R.Cowan,
J.E.Matthews,
R.Mcmenamin,
D.M.Smith,
M.Vinković,
N.G.Wallis.
|
|
|
Ref.
|
|
J Med Chem, 2008,
51,
183-186.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
