SAR study of bicyclo[4.1.0]heptanes as melanin-concentrating hormone receptor R1 antagonists: Taming hERG

Bioorganic and Medicinal Chemistry

Volumn 15, Issue 16, 2007, Pages 5369-5385

  Su, Jing ^a   McKittrick, Brian A ^a   Tang, Haiqun ^a   Burnett, Duane A ^a   Clader, John W ^a   Greenlee, William J ^a   Hawes, Brian E ^a   O'Neill, Kim ^a   Spar, Brian ^a   Weig, Blair ^a   Kowalski, Timothy ^a   Sorota, Steve ^a   Li, Cheng ^a   Liu, Tongtong ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Ex vivo activity; hERG; Melanin concentrating hormone receptor R1 antagonist; Parallel synthesis

Indexed keywords

BICYCLO[4.1.0]HEPTANE; FUSED ALICYCLIC COMPOUND; HORMONE RECEPTOR BLOCKING AGENT; MELANIN CONCENTRATING HORMONE R 1 RECEPTOR ANTAGONIST; POTASSIUM CHANNEL HERG; UNCLASSIFIED DRUG;

ALKALINITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG BINDING SITE; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SYNTHESIS; EX VIVO STUDY; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANIMALS; CYCLOHEPTANES; DNA-BINDING PROTEINS; MICE; MOLECULAR STRUCTURE; RECEPTORS, PITUITARY HORMONE; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATORS;

EID: 34250722786     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmc.2007.05.068     Document Type: Article

References (42)

1. For a review of current approaches for the treatment of obesity, see:. Fernández-López J., Remesar X., Foz M., and Alemany M. Drugs 62 (2002) 915-944
2. Bray G.A. J. Med. Chem. 49 (2006) 4001
3. Kawauchi H., Kawazoe I., Tsubokawa M., Kishida M., and Baker B.L. Nature 305 (1983) 321
4. Rossi M., Choi S., O'Shea D., Miyoshi T., Ghatei M.A., and Bloom S.R. Endocrinology 138 (1997) 351
5. Qu D., Ludwig D.S., Gammeltoft S., Piper M., Pelleymounter M., Cullen M.J., Mathes W.F., Przypek J., Kanarek R., and Maratos-Flier E. Nature 380 (1996) 243
6. Ludwig D.S., Tritos N.A., Mastaitis J.W., Kulkarni R., Kokkotou E., Elmquist J., Lowell B., Flier J.S., and Maratos-Flier E. J. Clin. Invest. 107 (2001) 379
7. Shimada M., Tritos N., Lowell B., Flier J., and Maratos-Flier E. Nature 396 (1998) 670
8. Chambers J., Amers R.S., Bergsma D., Muir A., Fitzgerald L.R., Hervieu G., Dytko G.M., Foley J.J., Martin J., Liu W.-S., Park J., Ellis C., Ganguly S., Konchar S., Cluderay J., Leslie R., Wilson S., and Sarau H.M. Nature 400 (1999) 261
9. Saito Y., Nothacker H.P., Wang Z., Lin H.S., Leslie F., and Civelli O. Nature 400 (1999) 265
10. Sailer A.W., Sano H., Zeng Z., McDonald T., Pan J., Pong S.-S., Feighner S.D., Tan C.P., Fukami T., Iwaasa H., Hreniuk D.L., Morin N.R., Sadowski S.J., Ito M., Bansal A., Ky B., Figueroa D.J., Jiang Q., Austin C.P., MacNeil D.J., Ishihara A., Ihara M., Kanatani A., Van der Ploeg L.H.T., Howard A.D., and Liu Q. Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 7564-7569
11. Goodfellow, V.; Rowbottom, M.; Dyck, B. P.; Tamiya, J.; Zhang, M.; Grey, T. D. WO 04081005 A1, 2004.
12. For a recent review, see:. Handlon A.L., and Zhou H. J. Med. Chem. 49 (2006) 4017
13. Dyck B., Markison S., Zhao L., Tamiya J., Grey J., Rowbottom M.W., Zhang M., Vickers T., Sorensen K., Norton C., Wen J., Heise C.E., Saunders J., Conlon P., Madan A., Schwarz D., and Goodfellow V.S. J. Med. Chem. 49 (2006) 3753
14. Kym P.R., Souers A.J., Campbell T.J., Lynch J.K., Judd A.S., Iyengar R., et al. J. Med. Chem. 49 (2006) 2339
15. Kowalski T.J., Spar B.D., Weig B., Farley C., Cook J., Ghibaudi L., Fried S., O'Neil K., Del Vecchio R.A., McBriar M., Guzik H., Clader J., Hawes B.E., and Hwa J. Eur. J. Pharmacol. 535 (2006) 182-191
16. McBriar M.D., Guzik H., Shapiro S., Paruchova J., Xu R., Palani A., Clader J.W., Cox K., Greenlee W.J., Hawes B.E., Kowalski T.J., ONeil K., Spar B.D., Weig B., Weston D.J., Farley C., and Cook J. J. Med. Chem. 49 (2006) 2294
17. Palani A., Shapiro S., McBriar M.D., Clader J.W., Greenlee W.J., Spar B., Kowalski T.J., Farley C., Cook J., van Heek M., Weig B., O'Neil K., Graziano M., and Hawes B. J. Med. Chem. 48 (2005) 4746
18. Vasudevan A., LaMarche M.J., Blackburn C., Che J.L., Luchaco-Cullis C.A., Lai S., et al. Bioorg. Med. Chem. Lett. 15 (2005) 4174
19. Kym P.R., Iyengar R., Souers A.J., Lynch J.K., Judd A.S., Gao J., et al. J. Med. Chem. 48 (2005) 5888
20. McBriar M.D., Guzik H., Xu R., Paruchova J., Li S., Palani A., Clader J.W., Greenlee W.J., Hawes B., Kowalski T.J., O'Neil K., Spar B., and Weig B. J. Med. Chem. 48 (2005) 2274
21. Su J., McKittrick B.A., Tang H., Czarniecki M., Greenlee W.J., Hawes B.E., and O'Neill K. Bioorg. Med. Chem. 13 (2005) 1829
22. Vasudevan A., Wodka D., Verzal M.K., Andrew J., Gao J., Brodjian S., Fry D., Dayton B., Marsh K.C., Hernandez L.E., Ogiela C.A., Collins C.A., and Kym P.R. Bioorg. Med. Chem. Lett. 14 (2004) 4879
23. Arienzo R., Clark D.E., Cramp S., Daly S., Dyke H.J., Lockery P., Norman D., Roach A.G., Stuttle K., Tomlinson M., Wong M., and Wren S.P. Bioorg. Med. Chem. Lett. 14 (2004) 4099
24. Carpenter A.J., and Hertzog D.L. Exp. Opin. Therap. Patents 12 (2002) 1639
25. Borowsky B., Durkin M.M., Ogozalek K., Marzabadi M.R., DeLeon J., Lagu B., Heurich R., Lichtblau H., Shaposhnik Z., Daniewska I., Blackburn T.P., Branchek T.A., Gerald C., Vaysse P.J., and Forray C. Nat. Med. 8 (2002) 1039
26. Amgen: AMG 076, 2005.
27. Neurogen: NGD-4715, November 14, 2006.
28. Xu R., Li S., Paruchova J., McBriar M.D., Guzik H., Palani A., Clader J.W., Cox K., Greenlee W.J., Hawes B.E., Kowalski T.J., O'Neil K., Spar B.D., Weig B., and Weston D.J. Bioorg. Med. Chem. 14 (2006) 3285
29. Sorota S., Zhang X.-S., Margulis M., Tucker K., and Priestly T. Assay Drug Dev. Technol. 3 (2005) 47-57
30. Fivush A.M., and Wilson T.M. Tetrahedron Lett. 38 (1997) 7151
31. Among 70 isocyanates, 51 were aryl ones and 19 were alkyl ones. All alkyl products were inactive.
32. b 14.5 nM.
33. i of 7115 nM.
34. 9c.
35. The stability of this 2,6-dichloropyridine moiety was examined. For example, an analog of 23a with R as hydroxymethyl (in place of aminomethyl) was mixed with 10 equiv of N-acyl cysteine in 50% water/DMSO at 37 °C for 21 h. LC/MS spectrum showed only the starting material.
36. Jamieson C., Moir E.M., Rankovic Z., and Wishart G. J. Med. Chem. 49 (2006) 5029
37. Roy M.-L., Dumaine R., and Brown A.M. Circulation 94 (1996) 817-823
38. For example, compound 22d had apical (AP) → basal (BL) permeability of 4.1 nm/s and BL → AP permeability of 21 nm/s, efflux ratio of 5; compound 23b had AP → BL permeability of 2.2 nm/s and BL → AP permeability of 194 nm/s, efflux ratio of 88. A compound with efflux ratio over 2 is considered as a pgp substrate.
39. Teodori E., Dei S., Scapecchi S., and Gualtieri F. IL Farmaco 57 (2002) 385
40. Marcantoni E., Nobili F., Bartoli G., Bosco M., and Sambri L. J. Org. Chem. 62 (1997) 4183
41. Calculated values for pKa: 9.1, 8.3, log P 4.4, log D 2.0 (using ACD/Labs software).
42. Audinot V., Lahaye C., Suply T., Beauverger P., Rodriguez M., Galizzi J.-P., Fauchere J.-L., and Boutin J.A. Br. J. Pharma. 133 (2001) 3931