Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas

Journal of Medicinal Chemistry

Volumn 49, Issue 7, 2006, Pages 2294-2310

  McBriar, Mark D ^a   Guzik, Henry ^a   Shapiro, Sherry ^a   Paruchova, Jaroslava ^a   Xu, Ruo ^a   Palani, Anandan ^a   Clader, John W ^a   Cox, Kathleen ^a   Greenlee, William J ^a   Hawes, Brian E ^a   Kowalski, Timothy J ^a   O'Neill, Kim ^a   Spar, Brian D ^a   Weig, Blair ^a   Weston, Daniel J ^a   Farley, Constance ^a   Cook, John ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOBESITY AGENT; BICYCLO[3.1.0]HEXYLUREA DERIVATIVE; HORMONE RECEPTOR BLOCKING AGENT; MELANIN CONCENTRATING HORMONE; MELANIN CONCENTRATING HORMONE RECEPTOR 1 ANTAGONIST; MELANOCORTIN; N [5 (4 CYANOPHENYL)BICYCLO[3.1.0]HEX 2 YL] N' [4 FLUORO 3 (TRIFLUOROMETHYL)PHENYL] N [3 (4 METHYL 1 PIPERAZINYL)PROPYL]UREA; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING ASSAY; BODY WEIGHT; CENTRAL NERVOUS SYSTEM; CONTROLLED STUDY; DRUG EFFICACY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SYNTHESIS; ENERGY; FEEDING; FOOD INTAKE; HOMEOSTASIS; MALE; MOUSE; NONHUMAN; OBESITY; STRUCTURE ACTIVITY RELATION; WEIGHT GAIN;

ADMINISTRATION, ORAL; ANIMALS; ANTI-OBESITY AGENTS; BIOLOGICAL AVAILABILITY; BODY WEIGHT; BRAIN; CHO CELLS; CRICETINAE; CRICETULUS; EATING; HALF-LIFE; MALE; OBESITY; PHENYLUREA COMPOUNDS; PIPERAZINES; RADIOLIGAND ASSAY; RATS; RECEPTORS, SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP; TISSUE DISTRIBUTION; UREA;

EID: 33645657828     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050886n     Document Type: Article

References (51)

1. Hill, J. O.; Wyatt, H. R.; Reed, G. W.; Peters, J. C. Obesity and the Environment; Where Do We Go from Here? Science 2003, 299, 853-855.
2. Mokdad, A. H.; Ford, E. S.; Bowman, B. A.; Deitz, W. H.; Vinicor, F.; Bales, V. S.; Marks, J. S. Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001. JAMA 2003, 289, 76-79.
3. U.S. Department of Health and Human Services. The Surgeon General's Call to Action to Prevent and Decrease Overweight and Obesity 2001, Public Health Service; Office of the Surgeon General, Rockville, MD, 2001; www.surgeongeneral.gov/topics/obesity.
4. Gura, T. Obesity Drug Pipeline Not so Fat. Science 2003, 299, 849-852.
5. Sorbera, L. A.; Castaner, J.; Silvestre, J. S. Rimonabant hydrochloride: Antiobesity drug, aid to smoking cessation, treatment of alcohol dependency, cannabinoid CB1 antagonist. Drugs Future 2005, 30, 128-137.
6. Duhl, D. M.; Boyce, R. S. Obesity Therapeutics: Prospects and Perspectives. Ann. Rep. Med. Chem. 2003, 38, 239-248.
7. Baker, B. I. Melanin-concentrating hormone: a general vertebrate neuropeptide. Int. Rev. Cytol. 1991, 126, 1-47.
8. (a) Hanada, R.; Nakazato, M.; Matsukura, S.; Murakami, N.; Yoshimatsu, H.; Sakata, T. Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system. Biochem. Biophys. Res. Commun. 2000, 268, 88-91.
9. (b) Stricker-Krongrad, A.; Dimitrov, T.; Beck, B. Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats. Brain Res. Mol. Brain Res. 2001, 92, 43-48.
10. (c) Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.; Yumoto, M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Chronic intracerebroventricular infusion of MCH causes obesity in mice. Am. J. Physiol.: Endocrinol. Metab. 2003, 284, E583-E588.
11. (d) Ito, M.; Gomori, A.; Ishihara, A.; Oda, Z.; Mashiko, S.; Matsushita, H.; Yumoto, M.; Sano, H.; Tokita, S.; Moriya, M.; Iwaasa, H.; Kanatani, A. Characterization of MCH-mediated obesity in mice. Am. J. Physiol.: Endocrinol. Metab. 2003, 284, E940-E945.
12. Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.; Maratos-Flier, E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998, 396, 670-674.
13. (a) Tan, C. P.; Sano, H.; Iwaasa, H.; Pan, J.; Sailer, A. W.; Hreniuk, D. L.; Feighner, S. D.; Palyha, O. C.; Pong, S. S.; Figueroa, D. J.; Austin, C. P.; Jiang, M. M.; Yu, H.; Ito, J,; Ito, M.; Guan, X. M.; MacNeil, D. J.; Kanatani, A.; Van der Ploeg, L. H.; Howard, A. D. Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics 2002, 79, 785-792.
14. (b) Fried, S.; O'Neill, K.; Hawes, B. E. Cloning and characterization of rhesus monkey MCH-R1 and MCH-R2. Peptides 2002, 23, 1401-1408.
15. (a) Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhou, D.; Bednarek, M. A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard, A. D.; Van der Ploeg, L. H.; MacIntyre, D. E.; Hickey, G. J.; Strack, A. M. Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats. Eur. J. Pharmacol. 2003, 475, 37-47.
16. (b) Chen, Y.; Hu, C.; Hsu, C. K.; Zhang, Q.; Bi, C.; Asnicar, M.; Hsiung, H. M.; Fox, N.; Slieker, L. J.; Yang, D. D.; Heiman, M. L.; Shi, Y. Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 2002, 143, 2469-2477.
17. (c) Marsh, D. J.; Weingarth, D. T.; Novi, D. E.; Chen, H. Y.; Trumbauer, M. E.; Chen, A. S.; Guan, X. M.; Jiang, M. M.; Feng, Y.; Camacho, R. E.; Shen, Z.; Frazier, E. G.; Yu, H.; Metzger, J. M.; Kuca, S. J.; Shearman, L. P.; Gopal-Truter, S.; MacNeil, D. J.; Strack, A. M.; MacIntyre, D. E.; Van der Ploeg, L. H.; Qian, S. Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 3240-3245.
18. (a) McBriar, M. D.; Kowalski, T. J. Melanin-concentrating hormone as a therapeutic target. Ann. Rep. Med. Chem. 2005, 40, 119-133.
19. (b) Dyke, H.; Ray, N. C. Recent developments in the discovery of MCH-1R antagonists for the treatment of obesity - an update. Expert Opin. Ther. Pat. 2005, 15, 1303-1313.
20. (c) Shi, Y. Beyond skin color: emerging roles of melanin-concentrating hormone in energy homeostasis and other physiological functions. Peptides 2004, 25, 1605-1611.
21. (d) Browning, A. Recent developments in the discovery of melanin-concentrating hormone antagonists: novel antiobesity agents. Expert Opin. Ther. Pat. 2004, 14, 313-325.
22. (e) Kowalski, T. J.; McBriar, M. D. Therapeutic potential of melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. Expert Opin. Invest. Drugs 2004, 13, 1113-1122.
23. See ref 12. Also, AMG-076 (Amgen) is currently undergoing phase I clinical trials and is claimed to be orally active. No structure has been reported. Investigational Drugs Database. http://www.iddb3.com/. Updated May 11, 2005. Iddb ref 519061.
24. (a) Handlon, A. L.; Al-Barazanji, K. A.; Barvian, K. K.; Bighan, E. C.; Carlton, D. L.; Carpenter, A. J.; Cooper, J. P.; Daniels, A. J.; Garrison, D. T.; Goetz, A. S.; Green, G. M.; Grizzle, M. K.; Guo, Y. C.; Hertzog, D. L.; Hyman, C. E.; Ignar, D. M.; Peckham, G. E.; Speake, J. D.; Britt, C.; Swain, W. R Discovery of potent and selective MCH receptor-1 antagonists for the treatment of obesity. Presented at the 228th National Meeting of the American Chemical Society. Philadephia, PA, August, 2004; Abstract MEDI-193.
25. (b) Investigational Drugs Database. http://www.iddb3.com/. Updated May 6, 2005. Iddb ref 572384.
26. (a) Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.; Vasudevan, A.; Judd, A. S.; Mulhern, M.; Brodjian, S.; Dayton, B.; Shapiro, R.; Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R. Identification of 2-(4-Benzyloxyphenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-concentrating hormone receptor 1 antagonist for the treatment of obesity. J. Med. Chem. 2005, 48, 1318-1321.
27. (b) Souers, A. J.; Gao, J.; Wodka, D.; Judd, A. S.; Mulhern, M.; Napier, J. J.; Brune, M. E.; Bush, E. N.; Brodjian, S. J.; Dayton, B. D.; Shapiro, R.; Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of urea-based indazoles as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity. Bioorg. Med. Chem. Lett. 2005, 15, 2752-2757.
28. (c) Vasudevan, A.; Souers, A. J.; Freeman, J.; Verzal, M. K.; Gao, J.; Mulhern, M. M.; Wodka, D.; Lynch, J. K.; Engstrom, K. M.; Wagaw, S. H.; Brodjian, S.; Dayton, B. D.; Falls, D.; Bush, E.; Brune, M.; Shapiro, R. D.; Marsh, K. C.; Hernandez, L. E.; Collins, C. A.; Kym, P. R. Aminopiperidine indazoles as orally efficacious melanin concentrating hormone receptor-1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 5293-5297.
29. (a) Vasudevan, A.; LaMarche, M. J.; Blackburn, C.; Che, J. L.; Luchaco-Cullis, C. A.; Lai, S.; Marsilje, T. H.; Patane, M. A.; Souers, A. J.; Wodka, D.; Geddes, B.; Chen, S.; Brodjian, S.; Falls, D. H.; Dayton, B. D.; Bush, E.; Brune, M.; Shapiro, R. D.; Marsh, K. C.; Hernandez, L. E.; Sham, H. L.; Collins, C. A.; Kym, P. R. Identification of ortho-amino benzamides and nicotinamides as MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 4174-4179.
30. (b) Kym, P. R.; Iyengar, R.; Souers, A. J.; Lynch, J. K.; Judd, A. S.; Gao, J.; Freeman, J.; Mulhern, M.; Zhao, G.; Vasudevan, A.; Wodka, D.; Blackburn, C.; Brown, J.; Che, J. L.; Cullis, C.; Lai, S. J.; LaMarche, M.; Marsilje, T.; Roses, J.; Sells, T.; Geddes, B.; Govek, E.; Patane, M.; Fry, D.; Dayton, B. D.; Brodjian, S.; Falls, D.; Brune, M.; Bush, E.; Shapiro, R.; Knourek-Segel, V.; Fey, T.; McDowell, C.; Reinhart, G. A.; Preusser, L. C.; Marsh, K.; Hernandez, L.; Sham, H. L.; Collins, C. A. Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists. J. Med. Chem. 2005, 48, 5888-5891.
31. (c) Vasudevan, A.; Verzal, M. K.; Wodka, D.; Souers, A. J.; Blackburn, C.; Che, J. L.; Lai, S.; Brodjian, S.; Falls, D. H.; Dayton, B. D.; Govek, E.; Daniels, T.; Geddes, B.; Marsh, K. C.; Hernandez, L. E.; Collins, C. A.; Kym, P. R. Identification of aminopiperadine benzamides as MCHr1 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 3412-3416.
32. 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'Neill, K.; Graziano, M.; Hawes, B. E. Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity. J. Med. Chem. 2005, 48, 4746-4749.
33. (a) Preliminary communication: McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O'Neill, K.; Spar, B.; Weig, B. Discovery of bicycloalkyl urea melanin concentrating hormone receptor antagonists: orally efficacious antiobesity therapeutics. J. Med. Chem. 2005, 48, 2274-2277.
34. (b) Presented in part: McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani, A.; Shapiro, S.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O'Neill, K.; Spar, B.; Weig, B. Design and synthesis of orally efficacious melanin concentrating hormone (MCH) receptor antagonists as antiobesity therapeutics. Presented at the 229th National Meeting of the American Chemical Society, San Diego, CA, March, 2005; Abstract MEDI-009.
35. 2). Formation and application to organic synthesis. J. Am. Chem. Soc. 1965, 87, 1353-1364.
36. Luche, J.-L. Lanthanides in organic chemistry, 1. Selective 1,2 reductions of conjugated ketones. J. Am. Chem. Soc. 1978, 100, 2226-2227.
37. Dess, D. B.; Martin, J. C. Readily accessible 12-I-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. J. Org. Chem. 1983, 48, 4155-4156.
38. Klapars, A.; Huang, X.; Buchwald, S. L. A general and efficient copper catalyst for the amidation of aryl halides. J. Am. Chem. Soc. 2002, 124, 7421-7428.
39. Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Synthesis of β-chloro, β-bromo, and β-iodo α,β-unsaturated ketones. Can. J. Chem. 1982, 60, 210-223.
40. 2Y) for efficient cyclopropanation of olefins. J. Org. Chem. 2004, 69, 327-334.
41. Denmark, S. E.; Edwards, J. P. A comparison of (chloromethyl)- and (iodomethyl)zinc cyclopropanation reagents. J. Org. Chem. 1991, 56, 6974-6981.
42. Wolf, E.; Rossmanith, E.; Bartlett, R.; Schleyerbach, R. Preparation of 3,5-di-tert-butyl-4-hydroxybenzamides as antiinflammatories. DE 1988/3702755 A1.
43. 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'Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J. Bicyclic [4.1.0] heptanes as phenyl replacements for melanin concentrating hormone (MCH) receptor antagonists. Bioorg. Med. Chem. In press.
44. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. Characteristic physical properties and structural fragments of marked oral drugs. J. Med. Chem. 2004, 47, 224-232.
45. Korfmacher, W. A.; Cox, K. A.; Ng, K. J.; Veals, J.; Hsien, Y.; Wainhaus, S.; Broske, L.; Prelusky, D.; Nomeir, A.; White, R. E. Cassette-accelerated rapid rat screen: a systematic procedure for the doing and liquid chromatography/atomspheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery. Rapid Commun. Mass Spectrom. 2001, 15, 335-340.
46. Simonyi, M.; Maksay, G. The Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press: London, 1999; pp 420-421.
47. Baudoin, B.; Jimonet, P.; Maignan, S.; Achard, D.; Mailliet, P.; Laoui, A.; Nemecek, C. Preparation of 4-[(imidazolylmethyl)amino]chroman-8-carboxamides as protein farnesyltransferase inhibitors. WO 2001/009125.
48. http://www.cerep.fr/cerep/users/index.asp. Accessed Sep 2, 2005.
49. Kowalski, T. J.; Spar, B. D.; Weig, B.; Parley, C.; Cook, J.; Gao, J.; Henry, M.; Ghibaudi, L.; Fried, S.; O'Neill, K.; Del Vecchio, R.; McBriar, M. D.; Guzik, H.; Clader, J.; Hawes, B.; Hwa, J. Effects of a selective melanin-concentrating hormone 1-receptor antagonist on food intake and energy homeostasis in diet-induced obese mice. Eur. J. Pharmacol. In press.
50. Guzi, T. J.; Paruch, K.; Dwyer, M. P.; Doll, R. J.; Girijavallabhan, V. M.; Mallams, A.; Alvarez, C. S.; Keertikar, K. M.; Rivera, J.; Chan, T.-Y.; Madison, V.; Fischmann, T. O.; Dillard, L. W.; Tran, V. D.; He, Z. M.; James, R. A.; Park, H.; Paradkar, V. M.; Hobbs, D. W. Preparation of pyrazolopyrimidines as cyclin-dependent kinase inhibitors. WO 2004/022561.
51. Hawes, B. E.; Kil, E.; Green, B.; O'Neill, K.; Fried, S.; Graziano, M. P. The melanin-concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. Endocrinology 2000, 141, 4524-4532.