Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 1, 2011, Pages 288-293

  Gallant, Michel ^a   Beaulieu, Christian ^a   Berthelette, Carl ^a   Colucci, John ^a   Crackower, Michael A ^a   Dalton, Chad ^a   Denis, Danielle ^a   Ducharme, Yves ^a   Friesen, Richard W ^a   Guay, Daniel ^a   Gervais, Franois G ^a   Hamel, Martine ^a   Houle, Robert ^a   Krawczyk, Connie M ^a   Kosjek, Birgit ^b   Lau, Stephen ^a   Leblanc, Yves ^a   Lee, Ernest E ^a   Levesque, Jean Franois ^a   Mellon, Christophe ^a   Molinaro, Carmela ^a   Mullet, Wayne ^a   O'Neill, Gary P ^a   O'Shea, Paul ^a   Sawyer, Nicole ^a   Sillaots, Susan ^a   Simard, Daniel ^a   Slipetz, Deborah ^a   Stocco, Rino ^a   Sørensen, Dan ^a   Truong, Vouy Linh ^a   Wong, Elizabeth ^a   Wu, Jin ^a   Zaghdane, Helmi ^a   Wang, Zhaoyin ^a   more..

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Asthma; CRTH2 antagonist; DP2 antagonist; MK 7246; Respiratory diseases

Indexed keywords

CHEMOATTRACTANT; CHEMOATTRACTANT RECEPTOR HOMOLOGOUS MOLECULE EXPRESSED ON T HELPER 2 CELL; MK 7246; PROSTANOID RECEPTOR; RAMATROBAN; TM 30089; UNCLASSIFIED DRUG;

AREA UNDER THE CURVE; ARTICLE; DRUG CLEARANCE; DRUG HALF LIFE; DRUG STRUCTURE; ENANTIOMER; HUMAN; HUMAN TISSUE; MALE; NONHUMAN; RAT; RESPIRATORY TRACT DISEASE; SEQUENCE ANALYSIS; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ANIMALS; CARBOLINES; HUMANS; LUNG DISEASES; MACACA MULATTA; MICROSOMES, LIVER; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, IMMUNOLOGIC; RECEPTORS, PROSTAGLANDIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78650509769     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.11.015     Document Type: Article

References (39)

1. J.Z. Haeggström, A. Rinaldo-Matthis, C.E. Wheelock, and A. Wetterholm Biochem. Biophys. Res. Commun. 21 2010 135
2. T. Honda, Y. Tokura, Y. Miyachi, and K. Kabashima Curr. Drug Targets 2010 available online
3. R.L. Jones, M.A. Giembycz, and D.F. Woodward Br. J. Pharmacol. 158 2009 104
4. L. Walch, C. Labat, J.P. Gascard, V. de Montpreville, C. Brink, and X. Norel Br. J. Pharmacol. 126 1999 859
5. E. Lai, I. De Lepeleire, T.M. Crumley, F. Liu, L.A. Wenning, N. Michiels, E. Vets, G. O'Neill, J.A. Wagner, and K. Gottesdiener Clin. Pharmacol. Ther. 81 2007 849
6. K. Cheng, T.J. Wu, K.K. Wu, C.F. Sturino, K. Metters, K. Gottesdiener, S.D. Wright, Z. Wang, G. O'Neill, E. Lai, and M.G. Waters Proc. Natl. Acad. Sci. U.S.A. 103 2006 6682
7. C.F. Sturino, G. O'Neill, N. Lachance, M. Boyd, C. Berthelette, M. Labelle, L. Li, B. Roy, J. Scheigetz, N. Tsou, Y. Aubin, K.P. Bateman, N. Chauret, S.H. Day, J.F. Lévesque, C. Seto, J.H. Silva, L.A. Trimble, MC. Carriere, D. Denis, G. Greig, S. Kargman, S. Lamontagne, MC. Mathieu, N. Sawyer, D. Slipetz, W.M. Abraham, T. Jones, M. McAuliffe, H. Piechuta, D.A. Nicoll-Griffith, Z. Wang, R. Zamboni, R.N. Young, and K.M. Metters J. Med. Chem. 50 2007 794
8. H. Hirai, K. Tanaka, O. Yoshie, K. Ogawa, K. Kenmotsu, Y. Takamori, M. Ichimasa, K. Sugamura, M. Nakamura, S. Takano, and K. Nagata J. Exp. Med. 193 2001 255
9. A. Sood, and R. Arora J. Clin. Hypertens. 11 2009 685
10. E. Kostenis, and T. Ulven Trends Mol. Med. 12 2006 148
11. A. Miadonna, A. Tedeschi, C. Brasca, G. Folco, A. Sala, and R.C. Murphy J. Allergy Clin. Immunol. 85 1990 906
12. J.L. Huang, P.S. Gao, R.A. Mathias, T.C. Yao, L.C. Chen, M.L. Kuo, S.C. Hsu, B. Plunkett, A. Togias, K.C. Barnes, C. Stellato, T.H. Beaty, and S.K. Huang Hum. Mol. Genet. 13 2004 2691
13. R. Schuligoi, E. Sturm, P. Luschnig, V. Konya, S. Philipose, M. Sedej, M. Waldhoer, B.A. Peskar, and A. Heinemann Pharmacology 85 2010 372
14. R. Pettipher, and T.T. Hansel Drug News Perspect. 21 2008 317
15. P. Norman Expert Opin. Invest. Drugs 19 2010 947
16. M. Abramovitz, M. Adam, Y. Boie, M.C. Carrire, D. Denis, C. Godbout, S. Lamontagne, C. Rochette, N. Sawyer, N.M. Tremblay, M. Belley, M. Gallant, C. Dufresne, Y. Gareau, R. Ruel, H. Juteau, M. Labelle, N. Ouimet, and K.M. Metters Biochim. Biophys. Acta 1483 2000 285
17. N. Sawyer, E. Cauchon, A. Chateauneuf, R.P. Cruz, D.W. Nicholson, K.M. Metters, G.P. O'Neill, and F.G. Gervais Br. J. Pharmacol. 137 2002 1163
18. F.G. Gervais, R.P. Cruz, A. Chateauneuf, S. Gale, N. Sawyer, F. Nantel, K.M. Metters, and G.P. O'Neill J. Allergy Clin. Immunol. 108 2001 982
19. G. Monneret, S. Gravel, M. Diamond, J. Rokach, and W.S. Powell Blood 98 2001 1942
20. T. Ishizuka, T. Matsui, Y. Okamoto, A. Ohta, and M. Shichijo Cardiovasc. Drug Rev. 22 2004 71
21. i = 4.3 nM, Ref. 16a).
22. T. Ulven, and E. Kostenis J. Med. Chem. 48 2005 897
23. Arimura, A.; Kishino, J.; Tanimoto, N. Preparation of indole derivatives as PGD2 receptor antagonists. WO 2003/097042.
24. Tanimoto, N.; Hiramatsu, Y.; Mitsumori, S.; Inagaki, M. Preparation of indole derivatives as PGD2 receptor antagonists. WO2003/097598.
25. L.M. Tompkins, and A.D. Wallace J. Biochem. Mol. Toxicol. 21 2007 176
26. Z.Y. Zhang, and Y.N. Wong Curr. Drug Metab. 6 2005 241
27. A. Chen, D. Dubé, L. Dubé, S. Gagné, M. Gallant, M. Gaudreault, E. Grimm, R. Houle, P. Lacombe, S. Laliberté, S. Liu, D. MacDonald, B. Mackay, D. Martin, D. McKay, D. Powell, and J.-F. Lévesque Bioorg. Med. Chem. Lett. 20 2010 5074
28. D.E. Moore Drug Saf. 25 2002 345
29. L. Lankerani, and E.D. Baron J. Cutan. Med. Surg. 2004 424
30. Wang, Z., Indole derivatives as CRTH2 receptor antagonists. WO07019675 and WO10031182.
31. F.G. Gervais, N. Sawyer, R. Stocco, M. Hamel, C. Krawczyk, S. Sillaots, D. Denis, E. Wong, Z. Wang, M. Gallant, W.M. Abraham, D. Slipetz, M.A. Crackower, and G.P. O'Neill Mol. Phamacol. 79 2011 1
32. H. Juteau, Y. Gareau, and M. Labelle Tetrahedron Lett. 38 1997 1481
33. i of 40 should be >207 nM.
34. Compound 45 was prepared according to the synthetic sequence B using methyl 1-(1H-indol-3-yl)cyclopropanecarboxylate as stating material. Horwell, D. C.; McKiernan, M. J.; Osborne, S. Tetrahedron Lett. 1998, 39, 8729.
35. Compounds 46 and 47 were prepared from the propyl ester of MK-7246 (i.e. 55) by the action of t-BuOK and MeI followed by saponification and chiral resolution.
36. S.-I. Bascop, J.-Y. Laronze, and J. Sapi Synthesis 2002 1689
37. M. Salim, and A. Capretta Tetrahedron 56 2000 8063
38. A. Okano, S. Oishi, T. Tanaka, N. Fujii, and H. Ohno J. Org. Chem. 75 2010 3396
39. A. Onistschenko, and H. Stamm Chem. Ber. 122 1989 2397