Info Miscellaneous Mechanisms Macrophage migration inhibitory factor antagonists

Levels of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) are elevated in IBD patients. Transgenic animals which overexpress MIF are more susceptible to DSS-induced colitis,135 and either antibody blockade of MIF or genetic depletion in mice significantly ameliorates the DSS-induced inflammatory response in mice.136 MIF-deficient macrophages are hyporesponsive to LPS, show reduced activation of NFkB and the production of TNF-a, an effect which appears to be in part due to a downregulation of TLR4.

MIF possesses the unique ability to catalyze the tautomerization of D,L-dopachrome methyl esters into their corresponding indole derivatives. Compounds that block the active site either inhibit MIF activity directly or may force MIF into a conformation which prevents its binding to CD74.137 Despite the large structural diversity of MIF tautomerase inhibitors,138 few compounds appear to have been studied in animal models of disease. One ISO-1, compound 64,139 is a reportedly selective MIF tautomerase inhibitor (IC50b7 mM), which when administered to SDZ-treated mice (1mg per mouse per day intraperitoneally), markedly reduced clinical and histopathological features of diabetes (hyperglycemia and insulitis), to an extent that was comparable with that of an anti-MIF antibody.140 A number of MIF inhibitor candidates (AVP-13546, AVP-13748) are being clinically evaluated. When given orally to DSS-treated mice, AVP-13748 was effective at reducing the inflammation.141 The structure of AVP-13748 is currently not known but may be one of a series of quinoline 3-carbonitriles as recently claimed.142 TRPV1 antagonists

One of the symptoms in IBD is abdominal pain. Additional neurogenic mechanisms have been also implicated in the induction of IBD. For instance, substance P receptors exhibit dramatic increases in binding in the colons of both CD and UC patients. TRPV1 is a nonselective cation channel, expressed on nerve terminals of intrinsic and extrinsic afferent neurons innervating the GI tract. TRPV1 plays a key role in the detection of noxious painful stimuli such as acid and heat, and TRPV1 _'_ mice have impaired inflammatory thermal hyperalgesia. Immunoreactive TRPV1 fibers increase in the submucosal plexus of diseased IBD tissue. On DSS-induced inflammation in Balb/c mice, the TRPV1 antagonist capsazepine (65) (2.5mgkg_ 1, twice daily intraperitoneally), significantly reduced the severity of inflammation and epithelial damage.143 Capsazepine was the first competitive TRPV1 antagonist identified, but since this discovery, several other series of compounds have been identified. Compounds such as A-425619 (66), which is 25-to 50-fold more potent at blocking TRPV1 activation (IC50 = 5 nM) than capsazepine,144 and GR-705498 (67) (pKB~ 7.6),145'146 which are more druglike, have been described and warrant further preclinical evaluation in IBD models.

The observation that blockade of TRPV1 channels appears to be effective at reducing colitic inflammation opens up a number of other avenues, including the modulation of afferent activity by tetrodotoxin-resistant Na channel blockers, calcitonin gene-related peptide receptor antagonists, substance P and neurokinin receptor antagonists, and neuropeptide Y receptor modulators, many of which have already been implicated in nociception and neurogenic inflammation, as well as attenuating DSS-induced colitis,147'148 but for which the limit of this review cannot cover.


1. Podolsky, D. K. N. Engl. J. Med. 2002, 347, 417-429.

2. Bouma, G.; Strober, W Nat. Rev. Immunol. 2003, 3, 521-533.

3. Russell, R. K.; Nimmo, E. R.; Satsangi, J. Curr. Opin. Genet. Devel. 2004, 14, 264-270.

4. Hugot, J. P; Chamaillard, M.; Zouali, H.; Lesage, S.; Cezard, J. P; Belaiche, J.; Almer, S.; Tysk, C.; O'Morain, C. A.; Gassull, M. et al. Nature 2001, 411, 599-603.

5. Ogura, Y; Bonen, D. K.; Inohara, N.; Nicolae, D. L.; Chen, F F; Ramos, R.; Britton, H.; Moran, T; Karaliuskas, R.; Duerr, R. H. et al. Nature 2001, 411, 603-606.

6. Iwasaki, A.; Medzhitov, R. Nat. Immunol. 2004, 5, 987-995.

7. Abreu, M. T Curr. Opin. Gastroenterol. 2003, 19, 559-564.

8. Sundberg, J. P.; Elson, C. O.; Bedigian, H.; Birkenmeier, E. H. Gastroenterology 1994, 107, 1726-1735.

9. Franchimont, D.; Vermeire, S.; El Housni, H.; Pierik, M.; Van Steen, K.; Gustot, T; Quertinmont, E.; Abramowicz, M.; Van Gossum, A.; Deviere, J. et al. Gut 2004, 53, 987-992.

10. Cario, E.; Podolsky, D. K. Infect. Immunol. 2000, 68, 7010-7017.

11. Hawlisch, H.; Belkaid, Y; Baelder, R.; Hildeman, D.; Gerard, C.; Kohl, J. Immunity 2005, 22, 415-426.

12. Woodruff, T M.; Arumugam, T V; Shiels, I. A.; Reid, R. C.; Fairlie, D. P; Taylor, S. M. J. Immunol. 2003, 171, 5514-5520.

13. Lodes, M. J.; Cong, Y; Elson, C. O.; Mohamath, R.; Landers, C. J.; Targan, S. R.; Fort, M.; Hershberg, R. M. J. Clin. Invest. 2004, 113, 1296-1306.

14. Araki, A.; Kanai, T.; Ishikura, T; Makita, S.; Uraushihara, K.; Iiyama, R.; Totsuka, T; Takeda, K.; Akira, S.; Watanabe, M. J. Gastroenterol. 2005, 40, 16-23.

15. Garlanda, C.; Riva, F.; Polentarutti, N.; Buracchi, C.; Sironi, M.; De Bortoli, M.; Muzio, M.; Bergottini, R.; Scanziani, E.; Vecchi, A. et al. Proc. Natl. Acad. Sci. USA 2004, 101, 3522-3526.

16. Lang, K. S.; Recher, M.; Junt, T.; Navarini, A. A.; Harris, N. L.; Freigang, S.; Odermatt, B.; Conrad, C.; Ittner, L. M.; Bauer, S. Nat. Med. 2005, 11, 138-145.

17. Panwala, C. M.; Jones, J. C.; Viney, J. L. J. Immunol. 1998, 161, 5733-5744.

18. Schwab, M.; Schaeffeler, E.; Marx, C.; Fromm, M. F; Kaskas, B.; Metzler, J.; Stange, E.; Herfarth, H.; Schoelmerich, J.; Gregor, M. et al. Gastroenterology 2003, 124, 26-33.

19. Brant, S. R.; Panhuysen, C. I.; Nicolae, D.; Reddy, D. M.; Bonen, D. K.; Karaliukas, R.; Zhang, L.; Swanson, E.; Datta, L. W; Moran, T. et al. Am. J. Hum. Genet. 2003, 73, 1282-1292.

20. Hammer, R. E.; Maika, S. D.; Richardson, J. A.; Tang, J. P; Taurog, J. D. Cell 1990, 63, 1099-1112.

21. Powrie, F; Uhlig, H. Novartis Found. Symp. 2004, 263, 164-174, discussion 174-178, 211-218.

22. Jurjus, A. R.; Khoury, N. N.; Reimund, J.-M. J. Pharmacol. Toxicol. Methods 2004, 50, 81-92.

23. Sandborn, W J.; Faubion, W A. Gut 2004, 53, 1366-1373.

24. Mannon, P. J.; Fuss, I. J.; Mayer, L.; Elson, C. O.; Sandborn, W J.; Present, D.; Dolin, B.; Goodman, N.; Groden, C.; Hornung, R. L. et al. N. Engl. J. Med. 2004, 351, 2069-2079.

25. Steidler, L.; Hans, W; Schotte, L.; Neirynck, S.; Obermeier, F; Falk, W; Fiers, W; Remaut, E. Science 2000, 289, 1352-1355.

26. Truelove, S. C.; Witts, L. J. Br. Med. J. 1955, 4947, 1041-1048.

27. Powell-Tuck, J.; Bown, R. L.; Lennard-Jones, J. E. Scand. J. Gastroenterol. 1978, 13, 833-837.

28. Schroeder, K. W; Tremaine, W J.; Ilstrup, D. M. N. Engl. J. Med. 1987, 317, 1625-1629.

29. Seo, M.; Okada, M.; Yao, T; Okabe, N.; Maeda, K.; Oh, K. Am. J. Gastroenterol. 1995, 90, 1759-1763.

30. Walmsley, R. S.; Ayres, R. C.; Pounder, R. E.; Allan, R. N. Gut 1998, 43, 29-32.

31. Harvey, R. F; Bradshaw, M. J. Lancet 1980, 1, 1134-1135.

32. Myren, J.; Bouchier, I. A.; Watkinson, G.; Softley, A.; Clamp, S. E.; de Dombal, F T Scand. J. Gastroenterol. 1984, 95, 1-27.

33. Daperno, M.; D'Haens, G.; Van Assche, G.; Baert, F; Bulois, P.; Maunoury, V; Sostegni, R.; Rocca, R.; Pera, A.; Gevers, A. et al. Gastrointest. Endosc. 2004, 60, 505-512.

34. Beaven, S. W; Abreu, M. T Curr. Opin. Gastroenterol. 2004, 20, 318-327.

35. Sandborn, W J.; Feagan, B. G.; Radford-Smith, G.; Kovacs, A.; Enns, R.; Innes, A.; Patel, J. Gut 2004, 53, 1485-1493.

36. Gordon, F H.; Lai, C. W; Hamilton, M. I.; Allison, M. C.; Srivastava, E. D.; Fouweather, M. G.; Donoghue, S.; Greenlees, C.; Subhani, J.; Amlot, P. L. et al. Gastroenterology 2001, 121, 268-274.

37. Gordon, F H.; Hamilton, M. I.; Donoghue, S.; Greenlees, C.; Palmer, T; Rowley-Jones, D.; Dhillon, A. P.; Amlot, P L.; Pounder, R. E. Aliment. Pharmacol. Ther. 2002, 16, 699-705.

38. Baert, F J.; D'Haens, G. R.; Peeters, M.; Hiele, M. I.; Schaible, T. F; Shealy, D.; Geboes, K.; Rutgeerts, P. J. Gastroenterology 1999,116, 22-28.

39. Louis, E.; Vermeire, S.; Rutgeerts, P; De Vos, M.; Van Gossum, A.; Pescatore, P; Fiasse, R.; Pelckmans, P.; Reynaert, H.; D'Haens, G. et al. Scand. J. Gastroenterol. 2002, 37, 818-824.

40. Siegel, C. A.; Sands, B. E. Aliment. Pharmacol. Ther. 2005, 22, 1-16.

41. Summers, R. W; Elliott, D. E.; Urban, J. F; Thompson, R. A.; Weinstock, J. V Gastroenterology 2005, 128, 825-832.

42. Cummings, J. H.; Kong, S. C. Novartis Found. Symp. 2004, 263, 99-111, discussion 111-114, 211-218.

43. Hoentjen, F; Harmsen, H. J.; Braat, H.; Torrice, C. D.; Mann, B. A.; Sartor, R. B.; Dieleman, L. A. Gut 2003, 52, 1721-1727.

44. Madsen, K. L.; Doyle, J. S.; Jewell, L. D.; Tavernini, M. M.; Fedorak, R. N. Gastroenterology 1999, 116, 1107-1114.

45. Osman, N.; Adawi, D.; Ahrne, S.; Jeppsson, B.; Molin, G. Dig. Dis. Sci. 2004, 49, 320-327.

46. Gionchetti, P.; Rizzello, F; Helwig, U.; Venturi, A.; Lammers, K. M.; Brigidi, P; Vitali, B.; Poggioli, G.; Miglioli, M.; Campieri, M. Gastroenterology 2003, 124, 1202-1209.

47. Fukata, M.; Michelsen, K. S.; Eri, R.; Thomas, L. S.; Hu, B.; Lukasek, K.; Nast, C. C.; Lechago, J.; Xu, R.; Naiki, Y et al. Gastrointest. Liver. Physiol. 2005, 288, G1055-G1065.

48. Hawkins, L. D.; Christ, W J.; Rossignol, D. P Curr. Topics Med. Chem. 2004, 4, 1147-1171.

49. Fort, M. M.; Mozaffarian, A.; Stover, A. G.; Correia Ida, S.; Johnson, D. A.; Crane, R. T.; Ulevitch, R. J.; Persing, D. H.; Bielefeldt-Ohmann, H.; Probst, P et al. J. Immunol. 2005, 174, 6416-6423.

51. Rachmilewitz, D.; Karmeli, F; Takabayashi, K.; Hayashi, T; Leider-Trejo, L.; Lee, J.; Leoni, L. M.; Raz, E. Gastroenterology 2002, 122, 1428-1441.

52. Rachmilewitz, D.; Katakura, K.; Karmeli, F; Hayashi, T; Reinus, C.; Rudensky, B.; Akira, S.; Takeda, K.; Lee, J.; Takabayashi, K. et al. Gastroenterology 2004, 126, 520-528.

53. Nikolaus, S.; Rutgeerts, P; Fedorak, R.; Steinhart, A. H.; Wild, G. E.; Theuer, D.; Mohrle, J.; Schreiber, S. Gut 2003, 52, 1286-1290.

54. Neurath, M. F; Pettersson, S.; Meyer zum Buschenfelde, K. H.; Strober, W Nat. Med. 1996, 2, 998-1004.

55. Chen, L. W; Egan, L.; Li, Z. W; Greten, F R.; Kagnoff, M. F; Karin, M. Nat. Med. 2003, 9, 575-581.

56. Yang, G.; McIntyre, K. W; Townsend, R. M.; Shen, H. H.; Pitts, W J.; Dodd, J. H.; Nadler, S. G.; McKinnon, M.; Watson, A. J. J. Immunol. 2003, 171, 6414-6420.

57. Nagamoto, H.; Maeda, T.; Harutta, J.-P; Miyakoda, G.; Mori, T; Tominaga, M. Gastroenterology 2004, 126, M1045, Abst.

58. Hartmann, G.; Bidlingmaier, C.; Siegmund, B.; Albrich, S.; Schulze, J.; Tschoep, K.; Eigler, A.; Lehr, H. A.; Endres, S. J. Pharmacol. Exp. Ther. 2000, 292, 22-30.

59. Burnouf, C.; Pruniaux, M. P Curr. Pharmaceut. Des. 2002, 8, 1255-1296.

60. Hanauer, S. B.; Miner, P. B.; Keshavarzian, A.; Isaacs, K.; Goff, J.; Harris, M. S. Gastroenterology 2004, 126, 814, Abst.

61. Doffinger, R.; Smahi, A.; Bessia, C.; Geissmann, F; Feinberg, J.; Durandy, A.; Bodemer, C.; Kenwrick, S.; Dupuis-Girod, S.; Blanche, S. et al. Nat. Genet. 2001, 27, 277-285.

62. McIntyre, K. W; Shuster, D. J.; Gillooly, K. M.; Dambach, D. M.; Pattoli, M. A.; Lu, P; Zhou, X. D.; Qiu, Y; Zusi, F C.; Burke, J. R. Arthritis Rheum. 2003 , 48, 2652-2659.

63. Murata, Y; Shimada, M.; Kadono, H.; Sakakibara, S.; Yoshino, T; Masuda, T; Shimazaki, M.; Shintani, T; Fuchikami, K.; Bacon, K. B. et al. Bioorg. Med. Chem. Lett. 2004, 14, 4013-4017.

64. Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Masuda, T; Shintani, T; Sato, H.; Koriyama, Y; Fukushima, K.; Nunami, N. Bioorg. Med. Chem. Lett. 2004, 14, 4019-4022.

65. Baxter, A.; Brough, S.; Cooper, A.; Floettmann, E.; Foster, S.; Harding, C.; Kettle, J.; McInally, T.; Martin, C.; Mobbs, M. Bioorg. Med. Chem. Lett. 2004, 14, 2817-2822.

66. Podolin, P. L.; Callahan, J. F; Bolognese, B. J.; Li, H. Y; Carlson, K.; Gregg Davis, T; Mellor, G. W; Evans, C.; Roshak, A. K. J. Pharmacol. Exp. Ther. 2005, 312, 373-381.

67. Ziegelbauer, K.; Gantner, F; Lukacs, N. W; Berlin, A.; Fuchikami, K.; Niki, T; Sakai, K.; Inbe, H.; Takeshita, K.; Ishimori, M. et al. Br. J. Pharmacol. 2005, 145, 178-192.

68. Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P. F.; Gilmore, T.; Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S. et al. Nat. Struct. Biol. 2002, 9, 268-272.

69. Hommes, D.; van den Blink, B.; Plasse, T; Bartelsman, J.; Xu, C.; Macpherson, B.; Tytgat, G.; Peppelenbosch, M.; Van Deventer, S. Gastroenterology 2002, 122, 7-14.

70. Brown, D. S.; Belfield, A. J.; Brown, G. R.; Campbell, D.; Foubister, A.; Masters, D. J.; Pike, K. G.; Snelson, W L.; Wells, S. L. Bioorg. Med. Chem. Lett. 2004, 14, 5383-5387.

71. Regan, J.; Capolino, A.; Cirillo, P F; Gilmore, T; Graham, A. G.; Hickey, E.; Kroe, R. R.; Madwed, J.; Moriak, M.; Nelson, R. et al. J. Med. Chem. 2003, 46, 4676-4686.

72. Loher, F; Bauer, C.; Landauer, N.; Schmall, K.; Siegmund, B.; Lehr, H. A.; Dauer, M.; Schoenharting, M.; Endres, S.; Eigler, A. J. Pharmacol. Exp. Ther. 2004, 308, 583-590.

73. Wannamaker, M., Davies, R. Prodrug of an ICE Inhibitor. PCT Patent W001/96003, Nov 29, 2001.

74. Popoff, I.; Jijon, H.; Monia, B.; Tavernini, M.; Ma, M.; McKay, R.; Madsen, K. J. Pharmacol. Exp. Therap. 2002, 303, 1145-1154.

75. Zingarelli, B.; Hake, P W; Burroughs, T. J.; Piraino, G.; O'Connor, M.; Denenberg, A. Immunology 2004, 113, 509-517.

76. Mazzon, E.; Dugo, L.; Li, J. H.; Di Paola, R.; Genovese, T; Caputi, A. P.; Zhang, J.; Cuzzocrea, S. Biochem. Pharmacol. 2002, 64, 327-337.

77. Southan, G. J.; Szabo, C. Curr. Med. Chem. 2003, 10, 321-340.

78. Massa, F; Marsicano, G.; Hermann, H.; Cannich, A.; Monory, K.; Cravatt, B. F; Ferri, G. L.; Sibaev, A.; Storr, M.; Lutz, B. J. Clin. Invest. 2004, 113, 1202-1209.

79. Kathuria, S.; Gaetani, S.; Fegley, D.; Valino, F; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; La Rana, G.; Calignano, A. et al. Nat. Med. 2003, 9, 76-81.

80. Porter, A. C.; Li, J.; Love, P L.; Shannon, H. E.; Li, D. L.; Phebus, L. A.; Gleason, S. D.; Witkin, J. M.; Simmons, J. M. A.; Iyengar, S. et al. Soc. Neurosci. Abstr. 2004, 34, Abs 273.11.

81. Leung, D.; Du, W; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt, B. F; Boger, D. L. Bioorg Med. Chem. Lett. 2005, 15, 1423-1428.

82. Rossi, A.; Kapahi, P; Natoli, G.; Takahashi, T; Chen, Y; Karin, M.; Santoro, M. G. Nature 2000, 403, 103-108.

83. Katayama, K.; Wada, K.; Nakajima, A.; Mizuguchi, H.; Hayakawa, T; Nakagawa, S.; Kadowaki, T; Nagai, R.; Kamisaki, Y; Blumberg, R. et al. Gastroenterology 2003, 124, 1315-1324.

84. Desreumaux, P; Dubuquoy, L.; Nutten, S.; Peuchmaur, M.; Englaro, W; Schoonjans, K.; Derijard, B.; Desvergne, B.; Wahli, W; Chambon, P et al. J. Exp. Med. 2001,193, 827-838.

85. Su, C. G.; Wen, X.; Bailey, S. T.; Jiang, W.; Rangwala, S. M.; Keilbaugh, S. A.; Flanigan, A.; Murthy, S.; Lazar, M. A.; Wu, G. D. J. Clin. Invest. 1999, 104, 383-389.

86. Dubuquoy, L.; Jansson, E. A.; Deeb, S.; Rakotobe, S.; Karoui, M.; Colombel, J. F; Auwerx, J.; Pettersson, S.; Desreumaux, P Gastroenterology 2003, 124, 1265-1276.

87. Lewis, J. D.; Lichtenstein, G. R.; Stein, R. B.; Deren, J. J.; Judge, T. A.; Fogt, F.; Furth, E. E.; Demissie, E. J.; Hurd, L. B.; Su, C. G. et al. Am. J. Gastroenterol. 2001, 96, 3323-3328.

88. Rousseaux, C.; Lefebvre, B.; Dubuquoy, L.; Lefebvre, P; Romano, O.; Auwerx, J.; Metzger, D.; Wahli, W; Desvergne, B.; Naccari, G. C. et al. J. Exp. Med. 2005, 201, 1205-1215.

89. Usui, S.; Suzuki, T; Hattori, Y; Etoh, K.; Fujieda, H.; Nishizuka, M.; Imagawa, M.; Nakagawa, H.; Kohda, K.; Miyata, N. Bioorg. Med. Chem. Lett. 2005, 15, 1547-1551.

90. Liu, K.; Black, R. M.; Acton, J. J., III; Mosley, R.; Debenham, S.; Abola, R.; Yang, M.; Tschirret-Guth, R.; Colwell, L.; Liu, C. et al. Bioorg. Med. Chem. Lett. 2005, 15, 2437-2440.

91. Berger, J. P.; Petro, A. E.; Macnaul, K. L.; Kelly, L. J.; Zhang, B. B.; Richards, K.; Elbrecht, A.; Johnson, B. A.; Zhou, G.; Doebber, T W et al. Mol. Endocrinol. 2003, 17, 662-676.

92. Berlin, C.; Berg, E. L.; Briskin, M. J.; Andrew, D. P; Kilshaw, P J.; Holzmann, B.; Weissman, I. L.; Hamann, A.; Butcher, E. C. Cell 1993, 74, 185-195.

93. Hesterberg, P E.; Winsor-Hines, D.; Briskin, M. J.; Soler-Ferran, D.; Merrill, C.; Mackay, C. R.; Newman, W; Ringler, D. J. Gastroenterology 1996, 111, 1373-1380.

94. Hokari, R.; Kato, S.; Matsuzaki, K.; Iwai, A.; Kawaguchi, A.; Nagao, S.; Miyahara, T; Itoh, K.; Sekizuka, E.; Nagata, H. et al. Clin. Exp. Immunol. 2001, 126, 259-265.

95. Tilley, J. W; Chen, L.; Sidduri, A.; Fotouhi, N. Curr. Topics Med. Chem. 2004, 4, 1509-1523.

96. Chang, L. L.; Truong, Q.; Mumford, R. A.; Egger, L. A.; Kidambi, U.; Lyons, K.; McCauley, E.; Van Riper, G.; Vincent, S.; Schmidt, J. A. Bioorg. Med. Chem. Lett. 2002, 12, 159-163.

97. Sircar, I.; Gudmundsson, K. S.; Martin, R.; Liang, J.; Nomura, S.; Jayakumar, H.; Teegarden, B. R.; Nowlin, D. M.; Cardarelli, P M.; Mah, J. R. Bioorg. Med. Chem. Lett. 2002, 10, 2051-2066.

98. Lin, L. S.; Lanza, T. J., Jr.; Castonguay, L. A.; Kamenecka, T; McCauley, E.; Van Riper, G.; Egger, L. A.; Mumford, R. A.; Tong, X.; MacCoss, M. et al. Bioorg. Med. Chem. Lett. 2004, 14, 2331-2334.

99. Hoshina, Y; Ikegami, S.; Okuyama, A.; Fukui, H.; Inoguchi, K.; Maruyama, T; Fujimoto, K.; Matsumura, Y; Aoyama, A.; Harada, T Bioorg. Med. Chem. Lett. 2005, 15, 217-220.

100. Egger, L. A.; Kidambi, U.; Cao, J.; Van Riper, G.; McCauley, E.; Mumford, R. A.; Amo, S.; Lingham, R.; Lanza, T; Lin, L. S. et al. J. Pharmacol. Exp. Ther. 2002, 302, 153-162.

101. Hijazi, Y; Welker, H.; Dorr, A. E.; Tang, J. P; Blain, R.; Renzetti, L. M.; Abbas, R. J. Clin. Pharmacol. 2004, 44, 1368-1378.

102. Berger, J. R.; Koralnik, I. J. N. Engl. J. Med. 2005, 353, 414-416.

103. Bowen-Yacyshyn, M. B.; Bennett, C. F; Nation, N.; Rayner, D.; Yacyshyn, B. R. J. Pharmacol. Exp. Ther. 2002, 302, 908-917.

104. Shimaoka, M.; Springer, T. A. Nat. Rev. Drug. Disc. 2003, 2, 703-716.

105. Potin, D.; Launay, M.; Nicolai, E.; Fabreguette, M.; Malabre, P.; Caussade, F; Besse, D.; Skala, S.; Stetsko, D. K.; Todderud, G. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1161-1164.

106. Winn, M.; Reilly, E. B.; Liu, G.; Huth, J. R.; Jae, H. S.; Freeman, J.; Pei, Z.; Xin, Z.; Lynch, J.; Kester, J. et al. J. Med. Chem. 2001, 44, 4393-4403.

107. Moser, B.; Wolf, M.; Walz, A.; Loetscher, P Trends Immunol. 2004, 25, 75-84.

108. Andres, P. G.; Beck, P L.; Mizoguchi, E.; Mizoguchi, A.; Bhan, A. K.; Dawson, T; Kuziel, W A.; Maeda, N.; MacDermott, R. P.; Podolsky, D. K. et al. J. Immunol. 2000, 164, 6303-6312.

109. Carson, K. G., Harriman, G. C. B. CCR1 Antagonists and Methods of Use Therefor. US Patent 0,106,639, Jun 3, 2004.

110. Liang, M.; Mallari, C.; Rosser, M.; Ng, H. P; May, K.; Monahan, S.; Bauman, J. G.; Islam, I.; Ghannam, A.; Buckman, B. et al. J. Biol. Chem. 2000, 275, 19000-19008.

111. Gladue, R. P. ; Tylaska, L. A. ; Brissette, W H . ; Lira, P. D. ; Kath, J. C . ; Poss, C . S . ; Brown, M . F ; Paradis, T J. ; Conklyn, M . J. ; Ogborne, K. T et al. J. Biol. Chem. 2003, 278, 40473-40480.

112. Ge, M.; Goble, S. D.; Pasternack, A.; Yang, L. 7 and 8 Membered Heterocyclic Cyclopentyl Benzylamide Modulators of Chemokine Receptor Activity. PCT Patent W02005/010154, 2005.

113. Butora, G.; Yang, L. L.; Goble, S. D. Tetrahydropyran Heterocyclic Cyclopentyl Heteroaryl Modulators of Chemokine Receptor Activity. PCT Patent W02005/014537, 2004.

114. Castagna, A.; Biswas, P; Beretta, A.; Lazzarin, A. Drugs 2005, 65, 879-904.

115. Rector, A.; Vermeire, S.; Thoelen, I.; Keyaerts, E.; Struyf, F; Vlietinck, R.; Rutgeerts, P; Van Ranst, M. Hum. Genet. 2001, 108, 190-193.

116. Arakaki, R.; Tamamura, H.; Premanathan, M.; Kanbara, K.; Ramanan, S.; Mochizuki, K.; Baba, M.; Fujii, N.; Nakashima, H. J. Virol. 1999, 73, 1719-1723.

117 . Gao, P ; Zhou, X. -Y ; Yashiro-Ohtani, Y ; Yang, Y -F ; Sugimoto, N . ; Ono, S . ; Nakanishi, T. ; Obika, S . ; Imanishi, T ; Egawa, T et al . J. Leukocyte Biol. 2003, 73, 273-280.

118. Tokuyama, H.; Ueha, S.; Kurachi, M.; Matsushima, K.; Moriyasu, F; Blumberg, R. S.; Kakimi, K. Int. Immunol. 2005, 17, 1023-1034.

119. Singh, U. P.; Singh, S.; Taub, D. D.; Lillard, J. W, Jr. J. Immunol. 2003, 171, 1401-1406.

120. Heise, C. E.; Pahuja, A.; Hudson, S. C.; Mistry, M. S.; Putnam, A. L.; Gross, M. M.; Gottlieb, P A.; Wade, W S.; Kiankarimi, M.; Schwarz, D. et al. J. Pharmacol. Exp. Ther. 2005, 313, 1263-1271.

121. Medina, J. C.; Johnson, M. G.; Li, A.-R.; Huang, A. X.; Zhu, L.; Marcus, A. P CXCR3 Antagonists. PCT Patent WO2002/083143, 2002.

122. Collins, T L.; Johnson, M. G.; Ma, J.; Medina, J. C.; Miao, S.; Schneider, M.; Tonn, G. R. CXCR3 Antagonists. PCT Patent WO2004/075863, 2004.

123. Papadakis, K. A.; Landers, C.; Prehn, J.; Kouroumalis, E. A.; Moreno, S. T; Gutierrez-Ramos, J. C.; Hodge, M. R.; Targan, S. R. J. Immunol. 2003, 171, 159-165.

124. Zabel, B. A.; Agace, W W; Campbell, J. J.; Heath, H. M.; Parent, D.; Roberts, A. I.; Ebert, E. C.; Kassam, N.; Qin, S.; Zovko, M. et al. J. Exp. Med. 1999, 190, 1241-1256.

125. Papadakis, K. A.; Prehn, J.; Moreno, S. T.; Cheng, L.; Kouroumalis, E. A.; Deem, R.; Breaverman, T.; Ponath, P. D.; Andrew, D. P.; Green, P. H. et al. Gastroenterology 2001, 121, 246-254.

126. Svensson, M.; Marsal, J.; Ericsson, A.; Carramolino, L.; Broden, T; Marquez, G.; Agace, W.W. J. Clin. Invest. 2002, 110, 1113-1121.

127. Mora, J. R.; Bono, M. R.; Manjunath, N.; Weninger, W; Cavanagh, L. L.; Rosemblatt, M.; Von Andrian, U. H. Nature 2003, 424, 88-93.

128. Fleming, P.; Harriman, G. C. B.; Shi, Z.; Chen, S. CCR9 Inhibitors and Methods of Use Therof. PCT Patent WO2003/099773, 2004.

129. Ugashe, S.; Zheng, W; Wright, J. J.; Pennel, A. Aryl Sulphonamides. PCT Patent WO2004/046092, 2004.

130. Iwata, M.; Hirakiyama, A.; Eshima, Y; Kagechika, H.; Kato, C.; Song, S. Y Immunity 2004, 21, 527-538.

132. Mizushima, T; Ito, T; Kishi, D.; Kai, Y; Tamagawa, H.; Nezu, R.; Kiyono, H.; Matsuda, H. Inflamm. Bowel Dis. 2004, 10, 182-192.

133. Shimizu, H.; Takahashi, M.; Kaneko, T.; Murakami, T.; Hakamata, Y.; Kudou, S.; Kishi, T.; Fukuchi, K.; Iwanami, S.; Kuriyama, K. et al. Circulation 2005, 111, 222-229.

134. Colandrea, V J.; Doherty, G. A.; Hale, J. J.; Lynch, C.; Mills, S. G.; Neway, W E.; Toth, L. 3-(2-Amino-1-Azacyclyl)-5-Aiyl-1,2,4-Oxadiazoles as S1P Receptor Agonists. PCT Patent WO2004/103279, 2004.

135. Ohkawara, T; Miyashita, K.; Nishihira, J.; Mitsuyama, K.; Takeda, H.; Kato, M.; Kondo, N.; Yamasaki, Y; Sata, M.; Yoshiki, T et al. Clin. Exp. Immunol. 2005, 140, 241-248.

136. de Jong, Y P; Abadia-Molina, A. C.; Satoskar, A. R.; Clarke, K.; Rietdijk, S. T.; Faubion, W A.; Mizoguchi, E.; Metz, C. N.; Alsahli, M.; ten Hove, T. et al. Nat. Immunol. 2001, 2, 1061-1066.

137. Leng, L.; Metz, C. N.; Fang, Y; Xu, J.; Donnelly, S.; Baugh, J.; Delohery, T; Chen, Y; Mitchell, R. A.; Bucala, R. J. Exp. Med. 2003, 191, 1467-1476.

138. Orita, M.; Yamamoto, S.; Katayama, N.; Fujita, S. Curr. Pharm. Des. 2002, 8, 1297-1317.

139. Lubetsky, J. B.; Dios, A.; Han, J.; Aljabari, B.; Ruzsicska, B.; Mitchell, R.; Lolis, E.; Al-Abed, Y J. Biol. Chem. 2002, 277, 24976-24982.

140. Cvetkovic, I.; Al-Abed, Y; Miljkovic, D.; Maksimovic-Ivanic, D.; Roth, J.; Bacher, M.; Lan, H. Y; Nicoletti, F; Stosic-Grujicic, S. Endocrinology 2005, 146, 2942-2951.

141. Ying, W; Li, X.; Baclig, R.; Scholz, W; Kumar, S.; Sircar, J. American Physiological Society; Translational Research Conference: Immunological and Pathophysiological Mechanisms in Inflammatory Bowel Disease Abstract 4.39. Sept. 8-11, 2004; Snowmass, Colorado.

142. Sircar, J.; Kumar, S.; Ying, W Inhibitors of Macrophage Migration Inhibitory Factor and Methods for Identifying the Same. PCT Patent W02004/074218, 2004.

143. Kimball, E. S.; Wallace, N. H.; Schneider, C. R.; D'Andrea, M. R.; Hornby, P. J. Neurogastroenterol. Motil. 2004, 16, 811-818.

144. El Kouhen, R.; Surowy, C. S.; Bianchi, B.; Neelands, T; McDonald, H.; Niforatos, W; Gomtsyan, A.; Lee, C.-H.; Honore, P; Sullivan, J. et al. J. Pharmacol. Exp. Ther. 2005, 414, 400-409.

145. Rami, H. K. In Anglo-Swedish Medicinal Chemistry, 2nd Symposium, Are Fjallby, Sweden, Mar 13-16, 2005.

146. Rami, H. K.; Thompson, M.; Wyman, P; Jerman, J. C.; Egerton, J.; Brough, S.; Stevens, A. J.; Randall, A. D.; Smart, D.; Gunthorpe, M. J. et al. Bioorg Med. Chem. Lett. 2004, 14, 3631-3634.

147. Hassani, H.; Lucas, G.; Rozell, B.; Ernfors, P Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, G550-G556.

148. Stucchi, A. F.; Shofer, S.; Leeman, S.; Materne, O.; Beer, E.; McClung, J.; Shebani, K.; Moore, F.; O'Brien, M.; Becker, J. M. Am. J. Physiol. Gastrointest. Liver. Physiol. 2000, 279, G1298-G1306.

149. Matsumoto, S.; Okabe, Y; Setoyama, H.; Takayama, K.; Ohtsuka, J.; Funahashi, H.; Imaoka, A.; Okada, Y; Umesaki, Y Gut 1998, 43, 71-78.

150. Podolsky, D. K.; Lobb, R.; King, N.; Benjamin, C. D.; Pepinsky, B.; Sehgal, P.; deBeaumont, M. J. Clin. Invest. 1993, 92, 372-380.

151. Maeda, S.; Hsu, L. C.; Liu, H.; Bankston, L. A.; Iimura, M.; Kagnoff, M. F; Eckmann, L.; Karin, M. Science 2005, 307, 734-738.

152. Wirtz, S.; Finotto, S.; Kanzler, S.; Lohse, A. W; Blessing, M.; Lehr, H. A.; Galle, P. R.; Neurath, M. F J. Immunol. 1999, 162, 1884-1888.

153. Powrie, F; Leach, M. W; Mauze, S.; Caddle, L. B.; Coffman, R. L. Int. Immunol. 1993, 5, 1461-1471.

154. Mashimo, H.; Wu, D. C.; Podolsky, D. K.; Fishman, M. C. Science 1996, 274, 262-265.

155. Kuhn, R.; Lohler, J.; Rennick, D.; Rajewsky, K.; Muller, W Cell 1993, 75, 263-274.

156. Shull, M. M.; Ormsby, I.; Kier, A. B.; Pawlowski, S.; Diebold, R. J.; Yin, M.; Allen, R.; Sidman, C.; Proetzel, G.; Calvin, D. et al. Nature 1992, 359, 693-699.

157. McDonald, S. A.; Palmen, M. J.; Van Rees, E. P.; MacDonald, T. T Immunology 1997, 91, 73-80.

158. Kontoyiannis, D.; Pasparakis, M.; Pizarro, T T; Cominelli, F; Kollias, G. Immunity 1999, 10, 387-398.

159. Hornquist, C. E.; Lu, X.; Rogers-Fani, P. M.; Rudolph, U.; Shappell, S.; Birnbaumer, L.; Harriman, G. R. Immunology 1997, 158, 1068-1077.

160. Esworthy, R. S.; Aranda, R.; Martin, M. G.; Doroshow, J. H.; Binder, S. W; Chu, F F Am. J. Physiol. Gastrointest. Liver. Physiol. 2001, 281, G848-G855.

161. Mizoguchi, A.; Mizoguchi, E.; Chiba, C.; Spiekermann, G. M.; Tonegawa, S.; Nagler-Anderson, C.; Bhan, A. K. J. Exp. Med. 1996, 183, 847-856.

162. Welte, T; Zhang, S. S.; Wang, T; Zhang, Z.; Hesslein, D. G.; Yin, Z.; Kano, A.; Iwamoto, Y; Li, E.; Craft, J. E. et al. Proc. Natl. Acad. Sci. USA 2003, 100, 1879-1884.


Nick Pullen graduated in biochemistry and chemistry and completed his PhD in G protein-coupled receptor signaling from the University of Southampton. From there he moved to the Novartis-funded Friedrich Miescher Institute in Basel, to pursue postdoctoral studies on signaling mechanisms involved in diabetes and oncology. He joined the Pfizer Gastrointestinal therapeutic area in 1999.

Jeremy D Gale has 17 years pharmaceutical industry experience in Discovery and Exploratory Development. He graduated in pharmacology and completed his PhD in pharmacology and neuroscience from the University of London. Jem commenced his career with Glaxo in 1988 to work in gastrointestinal pharmacology, ultimately leading their Discovery biology programs in reflux disease, irritable bowel syndrome, and emesis. He joined Pfizer in 1995 to lead Discovery Biology's Gastrointestinal research team and moved into Exploratory Clinical Development in 2002.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 613-642

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