Pyridinesulfonylureas and pyridinesulfonamides as selective bombesin receptor subtype-3 (BRS-3) agonists

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 7, 2011, Pages 2040-2043

  Lo, Michael M C ^a   Chobanian, Harry R ^a   Palyha, Oksana ^a   Kan, Yanqing ^a   Kelly, Theresa M ^a   Guan, Xiao Ming ^a   Reitman, Marc L ^a   Dragovic, Jasminka ^a   Lyons, Kathryn A ^a   Nargund, Ravi P ^a   Lin, Linus S ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Anti obesity drugs; Bombesin receptor subtype 3 (BRS 3) agonists; Orphan G protein coupled receptor; Pyridinesulfonamides; Pyridinesulfonylureas

Indexed keywords

1,1,3,3 TETRAMETHYLBUTYL; 1H PYRAZOLE 1 CARBOXAMIDINE; 2 FLUOROBENZENESULFONAMIDE; 4 (ALKYLOXY)PYRIDINE 3 SULFONAMIDE; 4 (EXO BICYCLO[2.2.1]HEPT 2 YLAMINO)PYRIDINE 3 SULFONAMIDE; 4 CHLOROPYRIDINE 3 SULFONAMIDE; ADAMANTYL; BICYCLO[2.2.1] HEPT 2 YLAMINE; BOMBESIN ANTAGONIST; BOMBESIN RECEPTOR; N METHYL TERT BUTYLAMINE; PYRIDINESULFONAMIDE DERIVATIVE; PYRIDINESULFONYLUREA DERIVATIVE; SULFONYLUREA; TERT BUTYLAMINE; TORASEMIDE; TRIMETHYLSILYLDIAZOMETHANE; UNCLASSIFIED DRUG;

ARTICLE; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; IC 50; NONHUMAN; NUCLEOPHILICITY;

ANIMALS; BIOLOGICAL AVAILABILITY; HYDROGEN BONDING; MALE; PYRIDINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, BOMBESIN; SULFONAMIDES; SULFONYLUREA COMPOUNDS;

BOVINE RESPIRATORY SYNCYTIAL VIRUS;

EID: 79952486290     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.02.011     Document Type: Article

References (36)

1. Anastasi, A.; Erspamer, V.; Bucci, M. Experientia 1971, 27, 166.
2. McDonald, T. J.; Jornvall, H.; Nilsson, G.; Vagne, M.; Ghatei, M.; Bloom, S. R.; Mutt, V. Biochem. Biophys. Res. Commun. 1979, 90, 227.
3. Minamino, N.; Kangawa, K.; Matsuo, H. Biochem. Biophys. Res. Commun. 1983, 114, 541.
4. (a) Moody, T. W.; Merali, Z. Peptides 2004, 25, 511;
5. (b) Ohki-Hamazaki, H.; Iwabuchi, M.; Maekawa, F. Int. J. Dev. Biol. 2005, 49, 293.
6. Jensen, R. T.; Battey, J. F.; Spindel, E. R.; Benya, R. V. Pharmacol. Rev. 2008, 60, 1.
7. (a) Liu, J.; Lao, Z. J.; Zhang, J.; Schaeffer, M. T.; Jiang, M. M.; Guan, X.-M.; Van der Ploeg, L. H. T.; Fong, T. M. Biochemistry 2002, 41, 8954;
8. (b) Sano, H.; Feighner, S. D.; Hreniuk, D. L.; Iwaasa, H.; Sailer, A. W.; Pan, J.; Reitman, M. L.; Kanatani, A.; Howard, A. D.; Tan, C. P. Genomics 2004, 84, 139.
9. Ohki-Hamazaki, H.; Watase, K.; Yamamoto, K.; Ogura, H.; Yamano, M.; Yamada, K.; Maeno, H.; Imaki, J.; Kikuyama, S.; Wada, E.; Wada, K. Nature 1997, 390, 165.
10. (a) Fathi, Z.; Corjay, M. H.; Shapira, H.; Wada, E.; Benya, R.; Jensen, R.; Viallet, J.; Sausville, E. A.; Battey, J. F. J. Biol. Chem. 1993, 268, 5979;
11. (b) Hou, X.; Wei, L.; Harada, A.; Tatamoto, K. Lung Cancer 2006, 54, 143;
12. (c) Tan, Y.-R.; Qi, M.-M.; Qin, X.-Q.; Xiang, Y.; Li, X.; Wang, Y.; Qu, F.; Liu, H.-J.; Zhang, J.-S. Peptides 2006, 27, 1852.
13. (a) Mantey, S. A.; Weber, H. C.; Sainz, E.; Akeson, M.; Ryan, R. R.; Pradhan, T. K.; Searles, R. P.; Spindel, E. R.; Battey, J. F.; Coy, D. H.; Jensen, R. T. J. Biol. Chem. 1997, 272, 26062;
14. (b) Mantey, S. A.; Coy, D. H.; Pradhan, T. K.; Igarashi, H.; Rizo, I. M.; Shen, L.; Hou, W.; Hocart, S. J.; Jensen, R. T. J. Biol. Chem. 2001, 276, 9219;
15. (c) Weber, D.; Berger, C.; Heinrich, T.; Eickelmann, P.; Antel, J.; Kessler, H. J. Peptide Sci. 2002, 8, 461;
16. (d) Boyle, R. G.; Humphries, J.; Mitchell, T.; Showell, G. A.; Apaya, R.; Iijima, H.; Shimada, H.; Arai, T.; Ueno, H.; Usui, Y.; Sakaki, T.; Wada, E.; Wada, K. J. Peptide Sci. 2005, 11, 136.
17. Weber, D.; Berger, C.; Eickelmann, P.; Antel, J.; Kessler, H. J. Med. Chem. 2003, 46, 1918.
18. Carlton, D. L.; Collin-Smith, L. J.; Daniels, A. J.; Deaton, D. N.; Goetz, A. S.; Laudeman, C. P.; Littleton, T. R.; Musso, D. L.; Morgan, R. J. O.; Szewczyk, J. R.; Zhang, C. Bioorg. Med. Chem. Lett. 2008, 18, 5451.
19. (a) He, S.; Dobbelaar, P. H.; Liu, J.; Jian, T.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo, C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Ruenz, M.; Sargent, B. J.; Yet, L.; Kelly, T. M.; Palyha, O.; Kan, Y.; Pan, J.; Chen, H.; Marsh, D. J.; Shearman, L. P.; Strack, A. M.; Metzger, J. M.; Feighner, S. D.; Tan, C.; Howard, A. D.; Tamvakopoulos, C.; Peng, Q.; Guan, X.-M.; Reitman, M. L.; Patchett, A. A.; Wyvratt, M. J.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, 1913;
20. (b) Liu, J.; He, S.; Jian, T.; Dobbelaar, P. H.; Sebhat, I. K.; Lin, L. S.; Goodman, A.; Guo, C.; Guzzo, P. R.; Hadden, M.; Henderson, A. J.; Pattamana, K.; Ruenz, M.; Sargent, B. J.; Swenson, B.; Yet, L.; Tamvakopoulos, C.; Peng, Q.; Pan, J.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Howard, A. D.; Marsh, D. J.; Metzger, J. M.; Reitman, M. L.; Wyvratt, M. J.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, 2074;
21. (c) Guo, C.; Guzzo, P. R.; Hadden, M.; Sargent, B. J.; Yet, L.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Rosko, K.; Gagen, K.; Metzger, J. M.; Dragovic, J.; Lyons, K.; Lin, L. S.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, 2785;
22. (d) Hadden, M.; Goodman, A.; Guo, C.; Guzzo, P. R.; Henderson, A. J.; Pattamana, K.; Ruenz, M.; Sargent, B. J.; Swenson, B.; Yet, L.; Liu, J.; He, S.; Sebhat, I. K.; Lin, L. S.; Tamvakopoulos, C.; Peng, Q.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X.-M.; Metzger, J. M.; Reitman, M. L.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20, 2912;
23. (e) Sebhat, I. K.; Franklin, C.; Lo, M. M.-C.; Chen, D.; Jewell, J. P.; Miller, R.; Pang, J.; Palyha, O.; Kan, Y.; Kelly, T. M.; Guan, X.-M.; Marsh, D. J.; Kosinski, J. A.; Metzger, J. M.; Lyons, K.; Dragovic, J.; Guzzo, P. R.; Henderson, A. J.; Reitman, M. L.; Nargund, R. P.; Wyvratt, M. J.; Lin, L. S. ACS Med. Chem. Lett. 2011, 2, 43.
24. (a) Guan, X.-M.; Chen, H.; Dobbelaar, P. H.; Dong, Y.; Fong, T. M.; Gagen, K.; Gorski, J.; He, S.; Howard, A. D.; Jian, T.; Jiang, M.; Kan, Y.; Kelly, T. M.; Kosinski, J.; Lin, L. S.; Liu, J.; Marsh, D. J.; Metzger, J. M.; Miller, R.; Nargund, R. P.; Palyha, O.; Shearman, L.; Shen, Z.; Stearns, R.; Strack, A. M.; Stribling, S.; Tang, Y. S.; Wang, S.-P.; White, A.; Yu, H.; Reitman, M. L. Cell Metab. 2010, 11, 101;
25. (b) Metzger, J. M.; Gagen, K.; Raustad, K. A.; Yang, L.; White, A.; Wang, S.-P.; Craw, S.; Liu, P.; Lanza, T.; Lin, L. S.; Nargund, R. P.; Guan, X.-M.; Strack, A. M.; Reitman, M. L. Am. J. Physiol. Endocrinol. Metab. 2010, 299, E816;
26. (c) Guan, X.- M.; Metzger, J. M.; Yang, L.; Raustad, K. A.; Wang, S.-P.; Spann, S. K.; Kosinski, J. A.; Yu, H.; Shearman, L. P.; Faidley, T. D.; Palyha, O.; Kan, Y.; Kelly, T. M.; Sebhat, I.; Lin, L. S.; Dragovic, J.; Lyons, K. A.; Craw, S.; Nargund, R. P.; Marsh, D. J.; Strack, A. M.; Reitman, M. L. J. Pharmacol. Exp. Ther. 2011, 336, 356.
27. 125I]-dY- peptide'.
28. 50 value determined with an internal standard. 100% activation is defined as the bioluminescence value obtained with 10 μM dY-peptide for human BRS-3 and 10 μM of a proprietary small-molecule standard for mouse BRS-3.
29. (a) Delarge, J. E.; Lapiere, C. L.; Georges, A. H. German Patent DE 2516025, 1975;
30. (b) Delarge, J. E.; Lapiere, C. L. Ann. Pharm. Fr. 1978, 36, 369.
31. 1H NMR and LC-MS.
32. The absolute stereochemistry of the amine was determined by stereospecific synthesis from (+)-endo-2-norborneol.
33. The blood samples were collected at various time points into lithium heparin tubes and centrifuged. The plasma samples were kept at -70 °C until analysis. The plasma samples were extracted by protein precipitation and analyzed by LC/MS/MS.
34. We used a mouse PD model to determine target engagement in the CNS from our compounds (see Ref. 13b for details of the model). Compound 2a was tested active at 10 mpk when dosed orally.
35. Sulfonamides with heterocycles lacking sterically demanding 3-substituents are inactive.
36. R = 11.4, 12.6 min.