Synthesis and structure-activity relationships of thieno[2,3-b]pyrroles as antagonists of the GnRH receptor

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 23, 2007, Pages 6448-6454

  Arnould, Jean Claude ^a   Delouvrié, Bénédicte ^a   Boutron, Pascal ^a   Dossetter, Al G ^a   Foote, Kevin M ^a   Hamon, Annie ^a   Hancox, Urs ^a   Harris, Craig S ^a   Hutton, Mike ^a   Lamorlette, Maryannick ^a   Matusiak, Zbigniew ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

Antagonist; GnRH; LHRH; Receptor; Thieno 2,3 b pyrrole

Indexed keywords

GONADORELIN ANTAGONIST; GONADORELIN RECEPTOR; THIENO[2,3 B]PYRROLE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG DISTRIBUTION; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ANIMALS; HUMANS; PYRROLES; RATS; RECEPTORS, LHRH; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 35648959817     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.09.099     Document Type: Article

References (40)

1. Matsuo H., Baba Y., Nair R.M.G., Arimura A., and Schally A.V. Biochem. Biophys. Res. Commun. 43 (1971) 1334
2. Amoss M., Burgus R., Blackwell R., Vale W., Fellows R., and Guillemin R. Biochem. Biophys. Res. Commun. 44 (1971) 205
3. Conn P.M., Janovick J.A., Stanislaus D., Kuphal D., and Jennes L. In: Litwack G. (Ed). Vitamins and Hormones Vol. 50 (1995), Academic Press, New York 151-214
4. Chengalvala M.V., Pelletier J.C., and Kopf G.S. Curr. Med. Chem.-Anticancer Agents 3 (2003) 399
5. Huirne J.A.F., and Lambalk C.B. Lancet 358 (2001) 1793
6. Herbst K. Curr. Opin. Pharmacol. 3 (2003) 660
7. Zhu Y.F., and Chen C. Expert Opin. Ther. Patents 14 (2004) 187
8. Cho N., Harada M., Toshihiro I., Imada T., Matsumoto H., Hayase Y., Sasaki S., Furuya S., Suzuki N., Okubo S., Ogi K., Endo S., Onda H., and Fujino M. J. Med. Chem. 41 (1998) 4190
9. Imada T., Cho N., Imaeda T., Hayase Y., Sasaki S., Kasai S., Harada M., Matsumoto H., Endo S., Suzuki N., and Furuya S. J. Med. Chem. 49 (2006) 3809
10. Ashton W.T., Sisco R.M., Kieczykowski G.R., Yang Y.T., Yudkovitz J.B., Cui J., Mount G.R., Ren R.N., Wu T.J., Shen X., Lyons K.A., Mao A.H., Carlin J.R., Karanam B.V., Vincent S.H., Cheng K., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 2597
11. Ashton W.T., Sisco R.M., Yang Y.T., Lo J.L., Yudkovitz J.B., Cheng K., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 1723
12. Ashton W.T., Sisco R.M., Yang Y.T., Lo J.L., Yudkovitz J.B., Gibbons P.H., Mount G.R., Ren R.N., Butler B.S., Cheng K., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 1727
13. Chu L., Hutchins J.E., Weber A.E., Lo J.L., Yang Y.T., Cheng K., Smith R.G., Fisher M.H., Wyvratt M.J., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 509
14. Chu L., Lo J.L., Yang Y.T., Cheng K., Smith R.G., Fisher M.H., Wyvratt M.J., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 515
15. Lin P., Marino D., Lo J.-L., Yang Y.T., Cheng K., Smith R.G., Fisher M.H., Wyvratt M.J., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 1073
16. Lin P., Parikh M., Lo J.-L., Yang Y.T., Cheng K., Smith R.G., Fisher M.H., Wyvratt M.J., and Goulet M.T. Bioorg. Med. Chem. Lett. 11 (2001) 1077
17. Young J., Huang S.X., Walsh T.F., Wyvratt M.J., Yang Y.T., Yudkovitz J.B., Cui J., Mount G.R., Ren R.N., Wu T.J., Shen X., Lyons K.A., Mao A.H., Carlin J.R., Karanam B.V., Vincent S.H., Cheng K., and Goulet M.T. Bioorg. Med. Chem. Lett. 12 (2002) 827
18. Simeone J.P., Bugianesi R.L., Ponpipom M.M., Yang Y.T., Lo J.L., Yudkovitz J.B., Cui J., Mount G.R., Ren R.N., Creighton M., Mao A.H., Vincent .H., Cheng K., and Goulet M.T. Bioorg. Med. Chem. Lett. 12 (2002) 3329
19. Zhu Y.-F., Gross T.D., Guo Z., Connors Jr. P.J., Gao Y., Tucci F.C., Struthers R.S., Reinhart G.J., Saunders J., Chen T.K., Bonneville A.L.K., and Chen C. J. Med. Chem. 46 (2003) 2023
20. Guo Z., Zhu Y.-F., Tucci F.C., Gao Y., Struthers R.S., Saunders J., Gross T.D., Xie Q., Reinhart G.J., and Chen C. Bioorg. Med. Chem. Lett. 13 (2003) 3311
21. Tucci F.C., Zhu Y.-F., Guo Z., Gross T.D., Connors Jr. P.J., Struthers R.S., Reinhart G.J., Saunders J., and Chen C. Bioorg. Med. Chem. Lett. 13 (2003) 3317
22. Guo Z., Chen Y., Wu D., Zhu Y.-F., Struthers R.S., Saunders J., Xie Q., and Chen C. Bioorg. Med. Chem. Lett. 13 (2003) 3617
23. Guo Z., Zhu Y.-F., Gross T.D., Tucci F.C., Gao Y., Moorjani M., Connors Jr. P.J., Rowbottom M.W., Chen Y., Struthers R.S., Xie Q., Saunders J., Reinhart G.J., Chen T.K., Killam Bonneville A.L., and Chen C. J. Med. Chem. 47 (2004) 1259
24. Rowbottom M.W., Tucci F.C., Zhu Y.-F., Guo Z., Gross T.D., Reinhart G.J., Xie Q., Struthers R.S., Saunders J., and Chen C. Bioorg. Med. Chem. Lett. 14 (2004) 2269
25. Tucci F.C., Zhu Y.-F., Guo Z., Gross T.D., Connors Jr. P.J., Gao Y., Rowbottom M.W., Struthers R.S., Reinhart G.J., Xie Q., Chen T.K., Bozigian H., Bonneville A.L.K., Fisher A., Jin L., Saunders J., and Chen C. J. Med. Chem. 47 (2004) 3483
26. Rowbottom M.W., Tucci F.C., Connors Jr. P.J., Gross T.D., Zhu Y.-F., Guo Z., Moorjani M., Acevedo O., Carter L., Sullivan S.K., Xie Q., Fisher A., Struthers R.S., Saunders J., Chen C., and Guo Z. Bioorg. Med. Chem. Lett. 14 (2004) 4967
27. Tucci F.C., Zhu Y.-F., Struthers R.S., Guo Z., Gross T., Rowbottom M.W., Acevedo O., Gao Y., Saunders J., Xie Q., Reinhart G.J., Liu X.-J., Ling N., Bonneville A.L.K., Chen T., and Chen C. J. Med. Chem. 48 (2005) 1169
28. Chen M., Guo Z., Lanier M.C., Zhao L., Betz S.F., Huang C.Q., Loweth C.J., Ashweek N.J., Liu X.-J., Struthers R.S., Bradbury M.J., Behan J.W., Wen J., O'Brien Z., Saunders J., and Zhu Y.-F. Bioorg. Med. Chem. Lett. 17 (2007) 3845
29. Foote, K. M.; Matusiak, Z.; Dossetter, A. G.; Arnould, J. C.; Lamorlette, M. A.; Delouvrié, B.; Hamon, A. WO 2004-018480, Chem. Abstr. 2004, 182888.
30. Arnould, J. C. WO 2004-018479, Chem. Abstr. 2004, 182887.
31. Garcia F., and Galvez C. Synthesis (1985) 143
32. Binder D., Habison G., and Noe C.R. Synthesis (1977) 487
33. Boche G. In: Paquette L.A. (Ed). Encyclopedia of Reagents for Organic Synthesis Vol. 4 (1995), Willey, New York 2240-2242
34. Shen Y., and Friestad G.K. J. Org. Chem. 67 (2002) 6236
35. Carpino L.A. J. Am. Chem. Soc. 115 (1993) 4397
36. 1H NMR spectroscopy.
37. 6 GnRH to receptors by 50%.
38. 50 value, which is the antagonist concentration, required to inhibit the GnRH stimulated LH release by 50%.
39. 50 was determined using 7-benzyloxy-4-(trifluoromethyl)-coumarin (BFC) as the substrate.
40. Chronic LH suppression. 12-week-old male AP Han Wistar rats were castrated. At least 10 days post surgery compound (75 mg/kg) or vehicle (ICME Imwitor 988 49%, Cremaphor RH40 27%, Miglyol 12%, ethanol 13%) alone was administered by oral gavage bid at a dose volume of 5 ml/kg. Terminal blood samples were taken 12 h after either the first or second dose. Plasma LH levels were measured by rat LH specific radioimmunoassay (Amersham). Inhibition is reported as a percentage of control plasma LH.