Synthesis and activity of 4,5-diarylimidazoles as human CB1 receptor inverse agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 5, 2005, Pages 1441-1446

  Plummer, Christopher W ^a   Finke, Paul E ^a   Mills, Sander G ^a   Wang, Junying ^a   Tong, Xinchun ^a   Doss, George A ^a   Fong, Tung M ^a   Lao, Julie Z ^a   Schaeffer, Marie Therese ^a   Chen, Jing ^a   Shen, Chun Pyn ^a   Stribling, D Sloan ^a   Shearman, Lauren P ^a   Strack, Alison M ^a   Van Der Ploeg, Lex H T ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Cannabinoid; CB1 inverse agonist; Imidazole; Obesity

Indexed keywords

2,3 DIHYDRO 5 METHYL 3 (MORPHOLINOMETHYL) 6 (1 NAPHTHOYL)PYRROLO[1,2,3 DE][1,4]BENZOXAZINE; 4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; CANNABINOID 1 RECEPTOR; CANNABINOID RECEPTOR AGONIST; RIMONABANT;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BODY WEIGHT; CONTROLLED STUDY; DRUG ACTIVITY; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; FOOD INTAKE; NONHUMAN; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION;

EID: 13944276316     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.12.078     Document Type: Article

References (29)

1. K.M. Flegal, M.D. Carroll, C.L. Ogden, and C.L. Johnson J. Am. Med. Assoc. 288 2002 1723
2. S.Z. Yanovski, and J.A. Yanovski New Engl. J. Med. 346 2002 591
3. For general reviews of cannabinoid receptor ligands and potential therapeutic applications, see: G. Di Carlo, and A.A. Izzo Exp. Opin. Invest. Drugs 12 2003 39
4. R.G. Pertwee Exp. Opin. Invest. Drugs 9 2000 1553
5. J.-N. Xiang, and J.C. Lee Annu. Rep. Med. Chem. 34 1999 199
6. R.C. Trillou, C. Arnone, N. Gonalons, P. Keane, J.P. Maffrand, and P. Soubrie J. Physiol. Regul. Integr. Comp. Physiol. 284 2003 345
7. M. Rinaldi-Carmona, F. Barth, M. Heaulme, D. Shire, B. Calandra, C. Congy, S. Martinez, J. Maruani, G. Neliat, D. Caput, P. Ferrarra, P. Soubrie, J.C. Breliere, and G. Le Fur FEBS Lett. 350 1994 240
8. F. Barth, and M. Rinaldi-Carmona Curr. Med. Chem. 6 1999 745
9. G. Colombo, R. Agabio, G. Diaz, C. Lobina, R. Reali, and G.L. Gessa Life Sci. 8 1998 113
10. R.G. Pertwee Pharmacol. Ther. 74 1997 129
11. B.K. Koe, G.M. Milne, A. Weissman, M.R. Johnson, and L.S. Melvin Eur. J. Pharmacol. 109 1985 201
12. S. Mato, A. Pazos, and E.M. Valdizan Eur. J. Pharmacol. 443 2002 43
13. R.S. Landsman, T.H. Burkey, P. Consroe, W.R. Roeske, and H.I. Yamamura Eur. J. Pharmacol. 1997 334R1 334R2
14. M. Bouaboula, S. Perrachon, L. Milligan, X. Canat, M. Rinaldi-Carmona, M. Portier, F. Barth, B. Calandra, F. Pecceu, J. Lupker, J.P. Maffrand, G. Le Fur, and P. Casellas J. Biol. Chem. 272 1997 22330
15. J.-Y. Shim, W.J. Welsh, E. Cartier, J.L. Edwards, and A.C. Howlett J. Med. Chem. 45 2002 1447
16. Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem., 2004; web release
17. Finke, P. E.; Meurer, L. C.; Debenham, J. S.; Toupence, R. B.; Walsh, T. F. WO Patent 03/082191 A2, 2003; Chem. Abstr. 2003, 139, 307686f
18. L.C. Meurer, P.E. Finke, S.G. Mills, T.F. Walsh, R.B. Toupence, J.S. Debenham, M.T. Goulet, J. Wang, X. Tong, T.M. Fong, J. Lao, M.-T. Schaeffer, J. Chen, C.-P. Shen, D.S. Stribling, L.P. Shearman, A.M. Strack, and L.H.T. Van der Ploeg Bioorg. Med. Chem. Lett. 15 2005 645
19. Barth, F.; Martinez, S.; Rinaldi-Carmona, M. WO Patent 03/084930 A1, 2003; Chem. Abstr., 2003, 139, 307689j
20. 1H NMR and/or MS data for all new compounds were in agreement with the assigned structures. For full experimental and representative NMR spectral data, see: Finke, P. E.; Mills, S. G.; Plummer, C. W.; Shah, S. K.; Truong, T. Q. WO Patent 03/007887-A2, 2003; Chem. Abstr. 2003, 138, 122647e
21. A small amount of unsubstituted N-H imidazole (<10%) was usually formed as a by-product from disproportionation of the N-methyl urea to urea during the reaction and was removed in subsequent purifications
22. Y.B. Kim, C.S. Kim, and C.K. Lee J. Heterocyclic Chem. 31 1994 1653
23. H. Bredereck, R. Gompper, H. Rempfer, K. Klemm, and H. Keck Chem. Ber. 92 1959 329
24. See the supplementary data for the NOE NMR spectral data for the structural assignment of 24b and 26b and the HMBC NMR experiment for the assignment of 28b and 29b
25. The reported binding results (±SD) were an average of 2-8 independent determinations (each done in replicate) which were normally within 50% of the average value based on a standard sample. For both the binding and functional assay conditions, see Ref. 21
26. C.C. Felder, K.E. Joyce, E.M. Briley, J. Mansouri, K. Mackie, O. Blond, Y. Lai, A.L. Ma, and R.L. Mitchell Mol. Pharmacol. 48 1995 443
27. See the supplementary data for a complete listing of CB2 binding data
28. Male Sprague-Dawley rats were dosed at 1.0 mg/kg iv via an implanted cannula (n = 1 (24b) or 2 (24a)) and at 2.0 mg/kg po by gavage (n = 3). Compounds were formulated at 1 mg/mL in TWEEN 80:EtOH:water (10:23:67) for both the iv and po doses. Plasma concentrations were determined by LC-MS/MS following protein precipitation
29. Male Sprague-Dawley rats were dosed at 1.0 mg/kg iv (n = 3 at each time point) via the tail vein. Compounds were formulated at 1 mg/mL in TWEEN 80:EtOH:water (10:23:67). Plasma and brain concentrations were determined by LC-MS/MS