Dihydroquinolines with amine-containing side chains as potent n-NOS inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 12, 2003, Pages 1981-1984

  Jaroch, Stefan ^a   Hölscher, Peter ^a   Rehwinkel, Hartmut ^a   Sülzle, Detlev ^a   Burton, Gerardine ^a   Hillmann, Margrit ^a   McDonald, Fiona M ^a  

^a Research Center Europe   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; DIHYDROQUINOLINE DERIVATIVE; NITRIC OXIDE SYNTHASE INHIBITOR;

ANALYTICAL PARAMETERS; ARTICLE; CHEMICAL STRUCTURE; DRUG POTENCY; DRUG SENSITIVITY; DRUG SYNTHESIS; ENZYME ASSAY; ENZYME INHIBITION; STRUCTURE ANALYSIS;

EID: 0038440630     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00351-2     Document Type: Article

References (46)

1. Huang Z., Huang P.L., Panahian N., Dalkara T., Fishman M.C., Moskowitz M.A. Science. 265:1994;1883 Holscher C. Trends Neurosci. 20:1997;298 Eliasson M.J.L., Huang Z., Ferrante R.J., Sasamata M., Molliver M.E., Snyder S.H., Moskowitz M.A. J. Neurosci. 19:1999;5910.
2. Huang Z., Huang P.L., Panahian N., Dalkara T., Fishman M.C., Moskowitz M.A. Science. 265:1994;1883 Holscher C. Trends Neurosci. 20:1997;298 Eliasson M.J.L., Huang Z., Ferrante R.J., Sasamata M., Molliver M.E., Snyder S.H., Moskowitz M.A. J. Neurosci. 19:1999;5910.
3. Huang Z., Huang P.L., Panahian N., Dalkara T., Fishman M.C., Moskowitz M.A. Science. 265:1994;1883 Holscher C. Trends Neurosci. 20:1997;298 Eliasson M.J.L., Huang Z., Ferrante R.J., Sasamata M., Molliver M.E., Snyder S.H., Moskowitz M.A. J. Neurosci. 19:1999;5910.
4. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
5. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
6. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
7. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
8. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
9. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
10. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
11. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
12. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
13. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
14. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
15. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
16. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
17. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
18. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
19. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.5
20. Reviews: Kerwin J.F., Lancaster J.R., Feldman P.L. J. Med. Chem. 38:1995;4343 Pfeiffer, S., Mayer, B., Hemmens, B. Angew. Chem. 1999, 111, 1824. Angew. Chem. Int. Ed. 1999, 38, 1714. Salerno L., Sorrenti V., Di Giacomo C., Romeo G., Siracusa M.A. Curr. Pharm. Des. 8:2002;177 Alcaraz M.J., Guillén M.I. Curr. Pharm. Des. 8:2002;215 Vallance P., Leiper J. Nature Rev. Drug Disc. 1:2002;939. For an overview of recent patent applications in the NOS field, see: Cheshire D.R. IDrugs. 4:2001;795 Lowe J.A. III IDrugs. 3:2000;63. Some recent literature reports on n-NOS inhibitors are: Beaton H., Hamley P., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1023 Beaton H., Boughton-Smith N., Hamley P., Ghelani A., Nicholls D.J., Tinker A.C., Wallace A.V. Bioorg. Med. Chem. Lett. 11:2001;1027 Hah J.-M., Roman L.J., Martásek P., Silverman R.B. J. Med. Chem. 44:2001;2677 Lee Y., Martásek P., Roman L.J., Silverman R.B. Bioorg. Med. Chem. Lett. 10:2000;2771 Huang H., Martásek P., Roman L.J., Silverman R.B. J. Med. Chem. 43:2000;2938 Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147 Lowe J.A. III, Qian W., Volkmann R.A., Heck S., Nowakowski J., Nelson R., Nolan C., Liston D., Ward K., Zorn S., Johnson C., Vanase M., Faraci W.S., Verdries K.A., Baxter J., Doran S., Sanders M., Ashton M., Whittle P., Stefaniak M. Biorg. Med. Chem. Lett. 9:1999;2569 Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858 Shearer B.G., Lee S., Oplinger J.A., Frick L.W., Garvey E.P., Furfine E.S. J. Med. Chem. 40:1997;1901.
21. Iadecola C., Zhang F., Xu S., Casey R., Ross M.E. J. Cereb. Blood Flow Metab. 15:1995;378 Iadecola C., Zhang F., Casey R., Nagayama M., Ross M.E. J. Neurosci. 17:1997;9157.
22. Iadecola C., Zhang F., Xu S., Casey R., Ross M.E. J. Cereb. Blood Flow Metab. 15:1995;378 Iadecola C., Zhang F., Casey R., Nagayama M., Ross M.E. J. Neurosci. 17:1997;9157.
23. Marletta M.A. J. Med. Chem. 37:1994;1899.
24. Jaroch S., Hölscher P., Rehwinkel H., Sülzle D., Burton G., Hillmann M., McDonald F.M. Bioorg. Med. Chem. Lett. 12:2002;2561.
25. Zhang Z.G., Reif D., Macdonald J., Tang W.X., Kamp D.K., Gentile R.J., Shakespeare W.C., Murray R.J., Chopp M. J. Cereb. Blood Flow Metab. 16:1996;599.
26. Collins J.L., Shearer B.G., Oplinger J.A., Lee S., Garvey E.P., Salter M., Duffy C., Burnette T.C., Furfine E.S. J. Med. Chem. 41:1998;2858.
27. Huang H., Martásek P., Roman L.J., Masters B.S.S., Silverman R.B. J. Med. Chem. 42:1999;3147.
28. This is in analogy to the Glaxo-Wellcome work.
29. Ried W., Käppler W. Liebigs Ann. Chem. 673:1964;132.
30. Bailey T.R. Tetrahedron Lett. 27:1986;4407.
31. This detour to establish a carboxyl group at C-7 is necessary, since the rigorous conditions of the dissolving metal reduction do not allow any functionalization of a C-7 substituent; for example, the 7-trifluoromethylquinolone is reduced to the 7-methyldihydroquinoline.
32. Carlsen P.H.J., Katsuki T., Martin V.S., Sharpless K.B. J. Org. Chem. 46:1981;3936 Kasai M., Ziffer H. J. Org. Chem. 48:1983;2346.
33. Carlsen P.H.J., Katsuki T., Martin V.S., Sharpless K.B. J. Org. Chem. 46:1981;3936 Kasai M., Ziffer H. J. Org. Chem. 48:1983;2346.
34. Kokotos G. Synthesis. 1990;299.
35. Ley S.V., Norman J., Griffith W.P., Marsden S.P. Synthesis. 1994;639.
36. Abdel-Magid A.F., Maryanoff C.A., Carson K.G. Tetrahedron Lett. 31:1990;5595.
37. Thomson I., Claussen K., Scheibye S., Lawesson S.-O. Org. Syn., Coll. VII:1990;372.
38. McKean D.R., Parrinello G., Renaldo A.F., Stille J.K. J. Org. Chem. 52:1987;422.
39. Dess D.B., Martin J.C. J. Am. Chem. Soc. 113:1991;7277.
40. Martinez G.R., Walker K.A.M., Hirschfeld D.R., Bruno J.J., Yang D.S., Maloney P.J. J. Med. Chem. 35:1992;620.
41. Mancuso A.J., Swern D. Synthesis. 1981;165.
42. 3N, DMF) cf.: Michelson J.W., Jacobsen E.J., Carter D.B., Im H.K., Im W.B., Schreur P.J.K.D., Sethy V.H., Tang A.H., McGee J.E., Pethe J.D. J. Med. Chem. 39:1996;4654.
43. 3N, DMF) cf.: Michelson J.W., Jacobsen E.J., Carter D.B., Im H.K., Im W.B., Schreur P.J.K.D., Sethy V.H., Tang A.H., McGee J.E., Pethe J.D. J. Med. Chem. 39:1996;4654.
44. 3N, DMF) cf.: Michelson J.W., Jacobsen E.J., Carter D.B., Im H.K., Im W.B., Schreur P.J.K.D., Sethy V.H., Tang A.H., McGee J.E., Pethe J.D. J. Med. Chem. 39:1996;4654.
45. Moore W.M., Webber R.K., Jerome G.M., Tjoeng F.S., Misko T.P., Currie M.G. J. Med. Chem. 37:1994;3886.
46. Bredt D.S., Snyder S.H. Proc. Natl. Acad. Sci. U.S.A. 87:1990;682.