Synthesis and Structure-Activity Relationships of Novel Arylpiperazines as Potent and Selective Agonists of the Melanocortin Subtype-4 Receptor

Journal of Medicinal Chemistry

Volumn 47, Issue 3, 2004, Pages 744-755

  Richardson, Timothy I ^a   Ornstein, Paul L ^a   Briner, Karin ^a   Fisher, Matthew J ^a   Backer, Ryan T ^a   Biggers, C Kelly ^a   Clay, Michael P ^a   Emmerson, Paul J ^a   Hertel, Larry W ^a   Hsiung, Hansen M ^a   Husain, Saba ^a   Kahl, Steven D ^a   Lee, Jonathan A ^a   Lindstrom, Terry D ^a   Martinelli, Michael J ^a   Mayer, John P ^a   Mullaney, Jeffery T ^a   O'Brien, Thomas P ^a   Pawlak, Joseph M ^a   Revell, Kevin D ^a   Shah, Jikesh ^a   Zgombick, John M ^a   Herr, R Jason ^b   Melekhov, Alex ^b   Sampson, Peter B ^b   King, Chi Hsin R ^b   more..

^a ELI LILLY AND COMPANY   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (DEXTRO TRICARBOXYLIC ACID 4 CHLOROPHENYLALANINE) 4 (2 ISOPROPYLPHENYL)PIPERAZINE; 1 (DEXTRO TRICARBOXYLIC ACID 4 CHLOROPHENYLALANINE) 4 [2 (IMIDAZOL 1 YLMETHYL)PHENYL]PIPERAZINE; 1 (DEXTRO TRICARBOXYLIC ACID 4 CHLOROPHENYLALANINE) 4 [2 [(DIMETHYLAMINO)METHYL]PHENYL]PIPERAZINE; 1 (DEXTRO TRICARBOXYLIC ACID 4 CHLOROPHENYLALANINE) 4 [2 [(METHYLSULFONYL)AMINO]PHENYL]PIPERAZINE; GUANINE NUCLEOTIDE BINDING PROTEIN; MELANOCORTIN 4 RECEPTOR; PEPTIDE LIBRARY; PIPERAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG EFFECT; DRUG IDENTIFICATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; EMBRYO; HUMAN; HUMAN CELL; NONHUMAN; PROTEIN TARGETING; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION; TREATMENT INDICATION;

ANIMALS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; CELL LINE; CYCLIC AMP; HUMANS; LIGANDS; PIPERAZINES; RADIOLIGAND ASSAY; RATS; RATS, INBRED F344; RECEPTOR, MELANOCORTIN, TYPE 4; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 9144220758     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0304109     Document Type: Article

References (31)

1. (a) Cone, R. D., Ed. The Melanocortin Receptors; Humana Press: Totowa, NJ, 2000, 551 pp.
2. (b) MacNeil, D. J.; Howard, A. D.; Guan, X.; Fong, T. M.; Nargund, R. P. ; Bednarek, M. A.; Goulet, M. T.; Weinberg, D. H.; Strack, A. M.; Marsh, D. J.; Chen, H. Y.; Shen, C.-P.; Chen, A. S.; Rosenblum, C. I.; MacNeil, T.; Tota, M.; MacIntyre, E. D.; Van der Ploeg, L. H. T. The role of melanocortins in body weight regulation: Opportunities for the treatment of obesity. Eur. J. Pharmacol. 2002, 440, 141-157.
3. (c) Wikberg, J. E. S. Melanocortin receptors: Perspectives for novel drugs. Eur. J. Pharmacol. 1999, 375, 295-310.
4. (a) Mountjoy, K. G.; Robbins, L. S.; Mortrud, M. T.; Cone, R. D. The cloning of a family of genes that encode the melanocortin receptors. Science 1992, 257, 1248-1251.
5. (b) Cone, R. D.; Mountjoy, K. G.; Robbins, L. S.; Nadeau, J. H.; Johnson, K. R.; Roselli-Rehfuss, L.; Mortrud, M. T. Cloning and functional characterization of a family of receptors for the melanotropic peptides. Ann. N. Y. Acad. Sci. 1993, 680, 342-363.
6. (c) Chhajlani, V.; Wikberg, J. E. S. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992, 309, 417-420.
7. (d) Gantz, I.; Konda, Y.; Tashiro, T.; Shimoto, Y.; Miwa, H.; Munzert, G.; Watson, S. J.; DelValle, J.; Yamada, T. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 1993, 268, 8246-8250.
8. (e) Mountjoy, K. G.; Mortrud, M. T.; Low, M. J.; Simerly, R. B.; Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 1994, 8, 1298-1308.
9. (f) Gantz, I.; Miwa, H.; Konda, Y.; Shimoto, Y.; Tashiro, T.; Watson, S. J.; DelValle, J.; Yamada, T. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 1993, 268, 15174-15179.
10. (g) Chhajlani, V.; Muceniece, R.; Wikberg, J. E. S. Molecular cloning of a novel human melanocortin receptor. Biochem. Biophys. Res. Commun. 1993, 195, 866-873.
11. (a) Chen, A. S.; Marsh, D. J.; Trumbauer, M. E.; Frazier, E. G.; Guan, X.-M.; Yu, H.; Rosenblum, C. I.; Vongs, A.; Feng, Y.; Cao, L.; Metzger, J. M.; Strack, A. M.; Camacho, R. E.; Mellin, T. N.; Nunes, C. N.; Min, W.; Fisher, J. ; Gopal-Truter, S.; MacIntyre, D. E.; Chen, H. Y.; Van der Ploeg, L. H. T. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nature Genet. 2000, 26, 97-102.
12. (b) Butler, A. A.; Kesterson, R. A.; Khong, K.; Cullen, M. J.; Pelleymounter, M. A.; Dekoning, J.; Baetscher, M.; Cone, R. D. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000, 141, 3518-3521.
13. (a) Herpin, T. F.; Yu, G.; Carlson, K. E.; Morton, G. C.; Wu, X.; Kang, L.; Tuerdi, H.; Khanna, A.; Tokarski, J. S.; Lawrence, R. M.; Macor, J. E. Discovery of Tyrosine-Based Potent and Selective Melanocortin-1 Receptor Small-Molecule Agonists with Antiinflammatory Properties. J. Med. Chem. 2003, 46, 1123-1126.
14. (b) Sebhat, I. K.; Martin, W. J.; Ye, Zhixiong; B. K.; Mosley, R. T.; Johnston, D. B. R.; Bakshi, R.; Palucki, B.; Weinberg, D. H.; MacNeil, T.; Kalyani, R. N.; Tang, R.; Stearns, R. A.; Miller, R. R.; Tamvakopoulos, C.; Strack, A. M.; McGowan, E.; Cashen, D. E.; Drisko, J. E.; Hom, G. J.; Howard, A. D.; MacIntyre, D. E.; Van der Ploeg, L. H. T.; Patchett, A. A.; Nargund, R. P. Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquino-linium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl) -2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist. J. Med. Chem. 2002, 45, 4589-4593.
15. (c) Pan, K.; Scott, M. K.; Lee, D. H. S.; Fitzpatrick, L. J.; Crooke, J. J.; Rivero, R. A.; Rosenthal, D. I.; Vaidya, A. H.; Zhao, B.; Reitz, A. B. 2,3-Diaryl-5-anilino-[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats. Bioorg. Med. Chem. 2003, 11, 185-192.
16. (d) Bondebjerg, J.; Xiang, Z.; Bauzo, R. M.; Haskell-Luevano, C.; Meldal, M. A Solid-Phase Approach to Mouse Melanocortin Receptor Agonists Derived from a Novel Thioether Cyclized Peptidomimetic Scaffold. J. Am. Chem. Soc. 2002, 124, 11046-11055.
17. (e) Joseph, C. G.; Bauzo, R. M.; Xiang, Z.; Haskell-Luevano, C. Urea small molecule agonists on mouse melanocortin receptors. Bioorg. Med. Chem. Lett. 2003, 13, 2079-2082.
18. (f) Mutulis, F.; Mutule, I.; Wikberg, J. E. S. N-Alkylamino acids and their derivatives interact with melanocortin receptors. Bioorg. Med. Chem. Lett. 2002, 12, 1039-1042.
19. (g) Mutulis, F.; Mutule, I.; Lapins, M.; Wikberg, J. E. S. Reductive amination products containing naphthalene and indole moieties bind to melanocortin receptors. Bioorg. Med. Chem. Lett. 2002, 12, 1035-1038.
20. Mayer, J. P. Discovery of Selective Melanocortin-4 Ligands through Combinatorial Modification of Privileged Structures. 18th American Peptide Symposium, July 19-23, 2003, Boston, MA.
21. Wolfe, J. P.; Buchwald, S. L. Scope and Limitations of the Pd/ BINAP-Catalyzed Amination of Aryl Bromides. J. Org. Chem. 2000, 65, 1144-1157.
22. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, V. J.; Loti, V. J.; Cerino, D. J.; Chen, P. J.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235-2246.
23. (b) Nargund, R. P.; Patchett, A. A.; Bach, M. A.; Murphy, M. G.; Smith, R. G. Peptidomimetic Growth Hormone Secretagogues. Design Considerations and Therapeutic Potential. J. Med. Chem. 1998, 41, 3103-3127.
24. (c) Patchett, A. A.; Nargund, R. P. Chapter 26. Privileged structures-An update. Ann. Rep. Med. Chem. 2000, 35, 289-298.
25. (a) Dyck, B. P.; Goodfellow, V.; Parker, J.; Phillips, T.; Wade, W.; Tran, J. A. Pyrroles as ligands of melanocortin receptors. PCT Int. Appl. WO2003068738, 2003.
26. (b) Boyce, R.; Chu, D. Guanidino compounds. PCT Int. Appl. WO2003066597, 2003.
27. (c) Dyck, B. P.; Goodfellow, V.; Phillips, T.; Parker, J.; Zhang, X.; Chen, C.; Tran, J. A.; Pontillo, J.; Tucci, F. C. Ligands of melanocortin receptors and compositions and methods related thereto. PCT Int. Appl. WO2003031410, 2003.
28. (d) Fotsch, C. H.; Arasasingham, P.; Bo, Y.; Chen, N.; Goldberg, M. H.; Han, N.; Hsieh, F.-Y.; Kelly, M. G.; Liu, Q.; Norman, M. H.; Smith, D. M.; Stec, M.; Tamayo, N.; Xi, N.; Xu, S. Substituted piperazines as modulators of the melanocortin receptor. PCT Int. Appl. WO2003009850, 2003.
29. (e) Carpino, P. A.; Cole, B. M.; Morgan, B. P. Melanocortin receptor ligands. PCT Int. Appl. WO2002000-654, 2002.
30. (f) Bakshi, R. K.; Barakat, K. J.; Nargund, R. P.; Palucki, B. L.; Patchett, A. A.; Sebhat, I.; Ye, Z.; Van Der Ploeg, L. H. T. Substituted piperidines as melanocortin-4 receptor agonists. PCT Int. Appl. WO2000074679, 2000.
31. (g) Nargund, R. P.; Ye, Z.; Palucki, B. L.; Bakshi, R. K.; Patchett, A. A.; Van Der Ploeg, L. H. T. Spiropiperidine derivatives as melanocortin receptor agonists. PCT Int. Appl. WO9964002, 1999.