Identification of orally bioavailable, non-amidine inhibitors of Urokinase Plasminogen Activator (uPA)

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 19, 2009, Pages 5712-5715

  West, Christopher W ^a   Adler, Marc ^a   Arnaiz, Danny ^a   Chen, Deborah ^a   Chu, Kieu ^a   Gualtieri, Giovanna ^a   Ho, Elena ^a   Huwe, Christoph ^a   Light, David ^a   Phillips, Gary ^a   Pulk, Rebecca ^a   Sukovich, Drew ^a   Whitlow, Marc ^a   Yuan, Shendong ^a   Bryant, Judi ^a  

^a BAYER AG   (Germany)

Author keywords

Serine protease; uPA; Urokinase

Indexed keywords

AMIDINE; PLASMINOGEN ACTIVATOR INHIBITOR;

ARTICLE; CHEMICAL MODIFICATION; DRUG BIOAVAILABILITY; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; AMIDINES; ANIMALS; BENZYLAMINES; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; RATS; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; UROKINASE-TYPE PLASMINOGEN ACTIVATOR;

EID: 69949087515     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.08.008     Document Type: Article

References (13)

1. Werb Z., Ashkenas J., MacAuley A., and Wiesen J.F. Braz. J. Med. Biol. Res. 29 (1996) 1087
2. Mignatti P., and Rifkin D.B. Physiol. Rev. 73 (1993) 161
3. Rockway T.W., Nienaber V., and Giranda V.L. Curr. Pharm. Des. 8 (2002) 2541
4. Bruncko M., McClellan W.J., Wendt M.D., Sauer D.R., Geyer A., Dalton C.R., Kaminski M.A., Weitzberg M., Gong J., Dellaria J.F., Mantei R., Zhao X., Nienaber V.L., Stewart K., Klinghofer V., Bouska J., Rockway T.W., and Giranda V.L. Bioorg. Med. Chem. Lett. 15 (2005) 93
5. Fish P.V., Barber C.G., Brown D.G., Butt R., Collis M.G., Dickinson R.P., Henry B.T., Horne V.A., Huggins J.P., King E., O'Gara M., McCleverty D., McIntosh F., Phillips C., and Webster R. J. Med. Chem. 50 (2007) 2341
6. Mackman R.L., Hui H.C., Breitenbucher J.G., Katz B.A., Luong C., Martelli A., McGee D., Radika K., Sendzik M., Spencer J.R., Sprengeler P.A., Tario J., Verner E., and Wang J. Bioorg. Med. Chem. Lett. 12 (2002) 2019
7. Joossens J., Ali O.M., El-Sayed I., Surpateanu G., Van der Veken P., Lambeir A., Setyono-Han B., Foekens J.A., Schneider A., Schmalix W., Haemers A., and Augustyns K. J. Med. Chem. 50 (2007) 6638
8. Frederickson M., Callaghan O., Chessari G., Congreve M., Cowan S.R., Matthews J.E., McMenamin R., Smith D.-M., Vinkovic M., and Wallis N.G. J. Med. Chem. 51 (2008) 183
9. Lottenberg R., Christensen U., Jackson C.M., and Coleman P.L. Methods Enzymol. 80 (1981) 341
10. Liang A.M., Light D.R., Kochanny M., Rumennik G., Trinh L., Lentz D., Post J., Morser J., and Snider M. Biochem. Pharmacol. 65 (2003) 1407
11. X-ray coordinates of compound 11 bound to uPA have been deposited into the Protein Data Bank (PDB identifier 3IG6).
12. Nienaber V., Davidson D., Edalji R., Giranda V.L., Klinghofer V., Henkin J., Magdalinos P., Mantei R., Merrick S., Severin J.M., Smith R.A., Stewart K., Walter K., Wang J., Wendt M., Weitzberg M., Zhao X., and Rockway T. Structure 8 (2000) 553
13. All final compounds were characterized by NMR, HPLC, MS, and EA. Additional synthetic details will be provided in future publications and patents.