2VIO

Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator

Summary for 2VIO

• Entry DOI: 10.2210/pdb2vio/pdb
• Related: 1C5W 1C5X 1C5Y 1C5Z 1EJN 1F5L 1F92 1FV9 1GI7 1GI8 1GI9 1GJ7 1GJ8 1GJ9 1GJA 1GJB 1GJC 1GJD 1KDU 1LMW 1O3P 1O5A 1O5B 1O5C 1OWD 1OWE 1OWH 1OWI 1OWJ 1OWK 1SC8 1SQA 1SQO 1SQT 1U6Q 1VJ9 1VJA 1W0Z 1W10 1W11 1W12 1W13 1W14 2JDE 2VIN 2VIP 2VIQ 2VIV 2VIW
• Descriptor: UROKINASE-TYPE PLASMINOGEN ACTIVATOR CHAIN B, ACETATE ION, 4-(2-aminoethoxy)-3,5-dichlorobenzoic acid, ... (4 entities in total)
• Functional Keywords: plasminogen activation, egf-like domain, blood coagulation, inhibitor, polymorphism, glycoprotein, fibrinolysis, kringle, zymogen, secreted, protease, hydrolase, urokinase-type plasminogen activator, pharmaceutical, serine protease, phosphorylation
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Secreted: P00749
• Total number of polymer chains: 1
• Total formula weight: 28753.47

Authors

Frederickson, M.,Callaghan, O.,Chessari, G.,Congreve, M.,Cowan, S.R.,Matthews, J.E.,McMenamin, R.,Smith, D.,Vinkovic, M.,Wallis, N.G. (deposition date: 2007-12-05, release date: 2008-01-22, Last modification date: 2017-07-05)

Primary citation

Frederickson, M.,Callaghan, O.,Chessari, G.,Congreve, M.,Cowan, S.R.,Matthews, J.E.,Mcmenamin, R.,Smith, D.,Vinkovic, M.,Wallis, N.G.
Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator
J.Med.Chem., 51:183-, 2008

PubMed 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.

PubMed: 18163548
DOI: 10.1021/JM701359Z

Experimental method

X-RAY DIFFRACTION (1.8 Å)