Novel thioamide derivatives as neutral CB1 receptor antagonists

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 2, 2010, Pages 479-482

  Boström, Jonas ^a   Olsson, Roine I ^a   Tholander, Joakim ^a   Greasley, Peter J ^a   Ryberg, Erik ^a   Nordberg, Henrik ^a   Hjorth, Stephan ^a   Cheng, Leifeng ^a  

^a ASTRAZENECA R AND D   (Sweden)

Author keywords

Cannabinoid 1; Conformational energy; DIO mice; Lawesson's reagent; Matched pairs; Neutral antagonist; Thioamide

Indexed keywords

5,6 DIARYLPYRAZINE 2 THIOAMIDE DERIVATIVE; CANNABINOID 1 RECEPTOR ANTAGONIST; RIMONABANT; THIOAMIDE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BODY WEIGHT; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG POTENCY; DRUG SOLUBILITY; DRUG SYNTHESIS; IN VITRO STUDY; MOUSE; NONHUMAN; OBESITY; ONE POT SYNTHESIS; WEIGHT REDUCTION;

ANIMALS; ANTI-OBESITY AGENTS; DISEASE MODELS, ANIMAL; MICE; MICE, OBESE; OBESITY; PYRAZINES; RECEPTOR, CANNABINOID, CB1; STRUCTURE-ACTIVITY RELATIONSHIP; THIOAMIDES;

MUS;

EID: 72549092662     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.11.125     Document Type: Article

References (31)

1. Sowers J.R. Am. J. Med. 115 (2003) 37
2. Bodkin J., Humphries E., and McLeod M. Aust. J. Chem. 56 (2003) 795
3. Heal D.J., Aspley S., Prow M.R., Jackson H.C., Martin K.F., and Cheetham S.C. Int. J. Obes. Relat. Metab. Disord. 22 (1998) S18
4. Leung W.Y., Neil T.G., Chan J.C., and Tomlinson B. Clin. Ther. 25 (2003) 58
5. Pertwee R.G. Addict. Biol. 5 (2000) 37
6. http://www.fda.gov/ohrms/dockets/ac/07/minutes/2007-4306m1-final.pdf.
7. http://www.emea.europa.eu/htms/human/withdraw/withdraw.htm.
8. Boström J., Berggren K., Elebring T., Greasley P.J., and Wilstermann M. Bioorg. Med. Chem. 15 (2007) 4077
9. Berggren, A. I. K.; Boström, S. J.; Elebring, T. S.; Fällefors, L.; Wilstermann, J. M.; Greasley, P. WO2004058255, 2004.
10. Berggren, A. I. K.; Boström, S. J.; Cheng, L.; Elebring, S. T.; Greasley, P.; Någård, M.; Wilstermann, J. M.; Terricabras, E. WO 2004058249, 2004.
11. Finke, P. E.; Meurer, L. C.; Debenham, J. S.; Toupence, R. B.; Walsh, T. F. WO 2003082191, 2003.
12. Barth, F.; Martinez, S.; Rinaldi Carmona, M. WO 2003084930, 2003.
13. Lange J.H.M., and Kruse C.G. Curr. Opin. Drug Discovery 7 (2004) 498
14. Reggio P.H. Curr. Pharm. Des. 9 (2003) 1607
15. Greasley P.J., and Clapham J.C. Eur. J. Pharmacol. 553 (2006) 1
16. Pertwee R.G. Life Sci. 76 (2005) 1307
17. rocs: OpenEye Scientific Software, Inc., 9 Bisbee Court, Suite D, Santa Fe, NM 87508, US.
18. Lecher H.Z., Greenwood R.A., Whitehouse K.C., and Chao T.H. J. Am. Chem. Soc. 78 (1956) 5018
19. Jesberger M., Davis T.P., and Barner L. Synthesis 13 (2003) 1929
20. 4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 25-80% ethyl acetate in heptane. The product fraction was concentrated under reduced pressure to give 2a in 54% yield.
21. All compounds in Table 1 were found to be outside the calibration range (i.e., log D >6.5) at pH 7.4. The lipophilicity (log D) values were determined by a HPLC LC/MS method described by Valko et al. (Valko, K.; Bevan, C.; Reynolds, D. Anal. Chem. 1997, 69, 2022).
22. The aqueous solubility data was measured in a consistent way from stored DMSO solutions.
23. Leach A.G., Jones H.D., Cosgrove D.A., Kenny P.W., Ruston L., MacFaul P., Wood J.M., Colclough N., and Law B. J. Med. Chem. 49 (2006) 6672
24. Wiberg K.B., and Rablen P.R. J. Am. Chem. Soc. 117 (1995) 2201
25. Jaguar, version 7.5; release 207, Schrödinger, LLC: New York, NY, 2008.
26. Becke A.D.J. Chem. Phys. 98 (1993) 5648
27. Lee C., Yang W., and Parr R.G. Phys. Rev. B: Condens. Matter 37 (1988) 785
28. Boström J., Norrby P.-O., and Liljefors T. J. Comput. Aided Mol. Des. 12 (1998) 383
29. Lee H.-J., Choi Y.-S., Lee K.-B., Park J., and Yoon C.-J. J. Phys. Chem. 106 (2002) 7010
30. Gardner A., and Mallet P.E. Eur. J. Pharmacol. 530 (2006) 103
31. The C57Bl/6 mice were purchased from Harlan Laboratories (Horst, the Netherlands).