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