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A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes

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Abstract

A neurokinin 2 (NK2) antagonist pharmacophore model has been developed on the basis of five non-peptide antagonists from several structurally diverse classes. To evaluate the pharmacophore model, another 20 antagonists were fitted to the model. By use of exhaustive conformational analysis (MMFFs force field and the GB/SA hydration model) and least-squares molecular superimposition studies, 23 of the 25 antagonists were fitted to the model in a low energy conformation with a low RMS value. The pharmacophore model is described by four pharmacophore elements: Three hydrophobic groups and a hydrogen bond donor represented as a vector. The hydrophobic groups are generally aromatic rings, but this is not a requirement. The antagonists bind in an extended conformation with two aromatic rings in a parallel displaced and tilted conformation. The model was able to explain the enantioselectivity of SR48968 and GR159897.

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References

  1. Regioli, D., Boudon, A. and Fauchére, J.-L., Pharmacol. Rev., 46 (1994) 551.

    Google Scholar 

  2. File, S.E., Pharmacol., Biochem. Behav., 58 (1997) 747.

    Google Scholar 

  3. Nutt, D., Lancet, 352 (1998) 1644.

    Google Scholar 

  4. Raffa, R.B., Neurosci. Behav. Rev., 22 (1998) 789.

    Google Scholar 

  5. Schoor,_J.V., Joos, G.F., Chasson, B.L., Brouard, R.J. and Pauwels, R.A., Eur. Respir. J., 12 (1998).

  6. Sakurada, T., Sakurada, C., Tan-No, K. and Kisara, K., CNS Drugs, 28 (1999) 1997.

    Google Scholar 

  7. Bountra, C., Bunce, K., Dale, T., Gardner, C., Jordan, C., Twissell, D. and Ward, P., Eur. J. Pharmacol., 249 (1993) R3.

    Google Scholar 

  8. Sprecher, A.v., Gerspacher, M. and Anderson, G.P., Current Research in Rheumatoid Arthritis, 2 (1998) 49.

    Google Scholar 

  9. Lowe, J.A., Drozda, S.E., Snider, R.M., Longo, K.P., Zorn, S.H., Morrone, J., Jackson, E.R., McLean, S., Bryce, D.K., Bordner, J., Nagahisa, A., Kanai, Y., Suga, O. and Megumi, T., J. Med. Chem., 35 (1992) 2591.

    Google Scholar 

  10. Gao, Z. and Peet, N.P., Curr. Med. Chem., 6 (1999) 375.

    Google Scholar 

  11. Gerspacher, M. and Sprecher, A.v., Drugs of the Future, 24(8) (1999) 883.

    Google Scholar 

  12. Desai, M.C., Lefkowitz, S.L., Thadeio, P.F., Longo, K.P. and Snider, R.M., J. Med. Chem., 35 (1992) 4911.

    Google Scholar 

  13. Elliott, J.M., Broughton, H., Cascieri, M.A., Chicchi, G., Huscroft, I.T., Kurtz, M., MacLeod, A.M., Sadowski, S. and Stevenson, G.I., Bioorg. Med. Chem. Lett., 8 (1998) 1851.

    Google Scholar 

  14. Takeuchi, Y., Shands, E.F.B., Beusen, D.D. and Marshall, G.R., J. Med. Chem., 41 (1998) 3609.

    Google Scholar 

  15. Swain, C.J., Seward, E.M., Cascieri, M.A., Fong, T.M., Herbert, R., MacIntyre, D.E., Merchant, K.J., Owen, S.N., Owens, A.P., Sabin, V., Teall, M., VanNiel, M.B., Williams, B.J., Sadowski, S., Strader, C., Ball, R.G. and Baker, R., J. Med. Chem., 38 (1995) 4793.

    Google Scholar 

  16. Goldstein, S., Neuwels, M., Moureau, F., Berckmans, D., Lassoie, M.-A., Differding, E., Houssin, R. and Hénichart, J.-P., Lett. Pept. Sci., 2 (1995) 125.

    Google Scholar 

  17. Jacoby, E., Boudon, A., Kucharczyk, N., Michel, A. and Fauchere, J.-L., J. Recept. Signal Transduction Res., 17 (1997) 855.

    Google Scholar 

  18. Vedani, A., Briem, H., Dobler, M., Dollinger, H. and McMasters, D. R., J. Med. Chem., 43 (2000) 4416.

    Google Scholar 

  19. Singh, J. and Thornton, J.M., FEBS, 191 (1985) 2989.

    Google Scholar 

  20. Williams, D.E., Acta Crystallographica, A36 (1980) 715.

    Google Scholar 

  21. Greenfeder, S., Cheewatrakoolpong, B., Billah, M., Egan, R.W., Keene, E., Murgolo, N.J. and Anthes, J.C., Bioorg. Med. Chem., 7 (1999) 2867.

    Google Scholar 

  22. Blaney, F.E., Raveglia, L.F., Artico, M., Cavagnera, S., Dartois, C., Farina, C., Grugni, M., Gagliardi, S., Luttmann, M.A., Martinelli, M., Nadler, G.M.M.G., Parini, C., Petrillo, P., Sarau, H.M., Scheideler, M.A., Hay, D.W.P. and Giardina, G.A.M., J. Med. Chem., 44 (2001) 1675.

    Google Scholar 

  23. Macromodel V6.5: Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrikson, T. and Still, W.C., J. Comput. Chem., 11 (1990) 440.

    Google Scholar 

  24. Chang, G., Guida, W.C. and Still, W.C., J. Am. Chem. Soc., 111 (1989) 4379.

    Google Scholar 

  25. Halgren, T.A., J. Comput. Chem., 20 (1999) 720.

    Google Scholar 

  26. Halgren, T.A., J. Comput. Chem., 20 (1999) 730.

    Google Scholar 

  27. Hasel, T.F., Hendrickson, T.F. and Still, W.C., Tetrahedron Comput. Method., 1 (1988) 103.

    Google Scholar 

  28. Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., J. Am. Chem. Soc., 112 (1990) 6127.

    Google Scholar 

  29. Boström, J., Norrby, P.-O. and Liljefors, T., J. Comput.-Aided Mol. Des., 12 (1998) 383.

    Google Scholar 

  30. McMartin, C. and Bohacek, R.S., J. Comput.-Aided Mol. Des., 9 (1995) 237.

    Google Scholar 

  31. McMartin, C. and Bohacek, R.S., J. Comput.-Aided Mol. Des., 11 (1997) 333. 286

    Google Scholar 

  32. Sjöberg, P., in Waterbeemd, H.v.d., Testa, B. and Folkers, G. (Eds.): Computer-Assisted Lead Finding and Optimization, Verlag Helvetica Chimica Acta, Basel 1997, p 83.

    Google Scholar 

  33. Spartan 5.0, Wavefunction, Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA 92612, 1997.

  34. Wu, E.S.C., Kover, A. and Semus, S.F., J. Med. Chem., 41 (1998) 4181.

    Google Scholar 

  35. Qi, H., Shah, S.K., Cascieri, M.A., Sadowski, S. and MacCoss, M., Bioorg. Med. Chem. Lett., 8 (1998) 2259.

    Google Scholar 

  36. Edmonds-Alt, X., Proietto, V., Broeck, D.V., Vilain, P., Advenier, C., Neliat, G., Fur, G.L. and Brelière, J.-C., Bioorg. Med. Chem. Lett., 3 (1993) 925.

    Google Scholar 

  37. Harrison, Korsgaard, M.P.G., Swain, C.J., Cascieri, M.A., Sadowski, S. and Seabrook, G.R., Bioorg. Med. Chem. Lett., 8 (1998) 1343.

    Google Scholar 

  38. Nishi, T., Fukazawa, T., Ishibashi, K., Nakajima, K., Sugioka, Y., Iio, Y., Kurata, H., Iyoh, K., Mukaiyama, O., Satoh, Y. and Yamaguchi, T., Bioorg. Med. Chem. Lett., 9 (1999) 875.

    Google Scholar 

  39. Schnorrenberg, G., Esser, F., Dollinger, H., Jung, B., Speck, G. and Buerger, E., DE4445939-A1.

  40. Selway, C.N. and Terrett, N.K., Bioorg. Med. Chem., 4 (1996) 645.

    Google Scholar 

  41. Kubota, H., Kakefuda, A., Nagaoka, H., Yamamoto, O., Ikeda, K., Takeuchi, M., Shibanuma, T. and Isomura, Y., Chem. Pharm. Bull., 46 (1998) 242.

    Google Scholar 

  42. Smith, P.W., Cooper, A.W.J., Bell, R., Beresford, I.J.M., Gore, P.M., McElroy, A.B., Pritchard, J.M., Saez, V., Taylor, N.R., Sheldrick, R.L.G. and Ward, P., J. Med. Chem., 38 (1995) 3772.

    Google Scholar 

  43. Cooper, A.W.J., Adams, H.S., Bell, R., Gore, P.M., McElroy, A.B., Pritchard, J.M., Smith, P.W. and Ward, P., Bioorg. Med. Chem. Lett., 4 (1994) 1951.

    Google Scholar 

  44. Jasseand, D., David, S., Antel, J., Brueckner, R., Eeckhout, C. and Bielenberg, G.-W., EP-899270-A1.

  45. MacKenzie, A.R., Marchington, A.P., Meadows, S.D. and Middleton, D.S., EP-791592-A2.

  46. Mackenzie, R.R., Marchington, A.P., Middelton, D.S. and Meadows, S.D., WO9727185-A1.

  47. Burkholder, T.P., Kudlacz, E.M., Le, T.-B. and Maynard, G.D., US5824690-A.

  48. Burkholder, T.P., Maynard, G.D. and Kudlacz, E.M., WO9827086-A1.

  49. Giardina, G.A.M., Grugni, M., Graziani, D. and Raveglia, L.F., WO-09852942.

  50. Miller, S.C., Jacobs, R.T. and Shenvi, A.B., EP-739891-A2.

  51. Monaghan, S.M., Alker, D. and Burns, C.J., WO9857972-A1.

  52. McCormick, K.D. and Lupo, A.T., WO-09639383.

  53. Shankar, B.B., US5688960-A.

  54. Shanker, B.B., WO-09818785.

  55. Shenvi, A.B., Jacobs, R.T., Miller, S.C., Macht, C.J. and Veale, C.A., WO-09516682.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark

    Anders Poulsen & Tommy Liljefors

  2. H. Lundbeck A/S, 9 Ottiliavej, DK-2500, Copenhagen-Valby, Denmark

    Anders Poulsen, Klaus Gundertofte & Berith Bjørnholm

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  1. Anders Poulsen
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  2. Tommy Liljefors
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  3. Klaus Gundertofte
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Correspondence to Tommy Liljefors.

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Poulsen, A., Liljefors, T., Gundertofte, K. et al. A pharmacophore model for NK2 antagonist comprising compounds from several structurally diverse classes. J Comput Aided Mol Des 16, 273–286 (2002). https://doi.org/10.1023/A:1020220306702

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