6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode

Journal of Medicinal Chemistry

Volumn 48, Issue 18, 2005, Pages 5684-5697

  Ulven, Trond ^a   Frimurer, Thomas M ^a   Receveur, Jean Marie ^a   Little, Paul Brian ^a   Rist, Øystein ^a   Nørregaard, Pia K ^a   Högberg, Thomas ^a  

^a 7TM Pharma A S   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

4 TRIFLUOROMETHOXYPHENOXYACETAMIDE; 6 ACYLAMINO 2 AMINOQUINOLINE DERIVATIVE; AMINOQUINOLINE DERIVATIVE; BENZAMIDE DERIVATIVE; MELANIN CONCENTRATING HORMONE; MELANIN CONCENTRATING HORMONE 1 RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG;

AMINO ACID SEQUENCE; ANIMAL CELL; ARTICLE; BINDING AFFINITY; COMPUTER MODEL; CONTROLLED STUDY; DRUG IDENTIFICATION; DRUG RECEPTOR BINDING; DRUG SCREENING; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HYPOTHESIS; NONHUMAN; PHARMACOPHORE; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

AMINOQUINOLINES; ANIMALS; BINDING SITES; CHO CELLS; CRICETINAE; CRICETULUS; HUMANS; MODELS, MOLECULAR; PHOSPHATIDYLINOSITOLS; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RADIOLIGAND ASSAY; RECEPTORS, SOMATOSTATIN; STEREOISOMERISM; TRANSFECTION;

EID: 24744461364     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050103y     Document Type: Article

References (67)

1. (a) Kopelman, P. G. Obesity as a medical problem. Nature 2000, 404, 635-643.
2. (b) International Association for the Study of Obesity (IASO) (http://www.iaso.org).
3. (a) Bray, G. A.; Tartaglia, L. A. Medicinal strategies in the treatment of obesity. Nature 2000, 404, 672-677.
4. (b) Fernández-López, J.-A.; Remesar, X.; Foz, M.; Alemany, M. Pharmacological approaches for the treatment of obesity. Drugs 2002, 62, 915-944.
5. (c) Astrup, A. Treatment of Obesity. In International Textbook of Diabetes Mellitus, 3rd ed.; DeFronzo, R. A., Ferrannini, E., Keen, H., Zimmet. P., Eds.; John Wiley & Sons: Chichester, U.K., 2004; pp 673-690.
6. (a) Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Seeley, R. J.; Baskin, D. G. Central nervous system control of food intake. Nature 2000, 404, 661-671.
7. (b) Dhillo, W. S.; Bloom, S. R. Hypothalamic peptides as targets for obesity. Curr. Opin. Pharmacol. 2001, 1, 651-655.
8. (c) Largent, B. L.; Robichaud, A. J.; Miller, K. J. Promise and progress of central G protein-coupled receptor modulators for obesity treatments. Ann. Rep. Med. Chem. 2002, 37, 1-10.
9. Reviews: (a) Forray, C. The MCH receptor family: feeding brain disorders? Curr. Opin. Pharmacol. 2003 3, 85-89.
10. (b) Hervieu, G. Melanin-concentrating hormone functions in the nervous system: food intake and stress. Expert Opin. Ther. Targets 2003, 7, 495-511.
11. (c) Kawano, H.; Honma, S.; Honma, A.; Horie, M.; Kawano, Y.; Hayashi, S. Melanin-concentrating hormone neuron system: the wide web that controls the feeding. Anat. Sci. Int. 2002, 77, 149-160.
12. Butler, A. A.; Cone, R. D. Knockout models resulting in the development of obesity. Trends Genet. 2001, 17, S50-S53.
13. (a) Presse, F.; Sorokovsky, I.; Max, J.-P.; Nicolaidis, S.; Nahon, J.-L. Melanin-concentrating hormone is a potent anorectic peptide regulated by food-deprivation and glucopenia in the rat. Neuroscience 1996, 71, 735-745.
14. (b) Qu, D.; Ludwig, D. S.; Gammeltoft, S.; Piper, M.; Pelleymounter, M. A.; Cullen, M. J.; Mathes, W. F.; Przypek, J.; Kanarek, R.; Maratos-Flier, E. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 1996, 380, 243-247.
15. (c) Rossi, M.; Choi, S. J.; O'Shea, D.; Miyoshi, T.; Ghatel, M. A.; Bloom, S. R. Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 1997, 138, 351-355.
16. 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.
17. Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.; Kokkotou, E.; Elmquist, J.; Lowell, B.; Flier, J. S.; Maratos-Flier, E. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. 2001, 107, 379-386.
18. (a) Monzon, M. E.; de Souza, M. M.; Izquierdo, L. A.; Izquierdo, I.; Barros, D. M.; de Barioglio, S. R. Melanin-concentrating hormone (MCH) modifies memory retention in rats. Peptides 1999, 20, 1517-1519.
19. (b) Varas, M.; Perez, M.; Monzon, M. E.; Rubiales de Barioglio, S. Melanin-concentrating hormone, hippocampal nitric oxide levels and memory retention. Peptides 2002, 23, 2213-2221.
20. (a) Monzon, M. E.; De Barioglio, S. R. Response to novelty after i.c.v. injection of melanin-concentrating hormone (MCH) in rats. Physiol. Behav. 1999, 67, 813-817.
21. (b) Kela, J.; Salmi, P.; Rimondini-Giorgini, R.; Heilig, M.; Wahlestedt, C. Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties. Regul. Pept. 2002, 114, 109-114.
22. Borowsky, B.; Durkin, M. M.; Ogozalek, K.; Marzabadi, M. R.; DeLeon, J.; Heurich, R.; Lichtblau, H.; Shaposhnik, Z.; Daniewska, I.; Blackburn, T. P.; Branchek, T. A.; Gerald, C.; Vaysse, P. J.; Forray, C. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat. Med. 2002, 8, 825-830.
23. Identification of MCH1R: (a) Chambers, J.; Ames, R. S.; Bergsma, D.; Muir, A.; Fitzgerald, L. R.; Hervieu, G.; Dytko, G. M.; Foley, J. J.; Martins, J.; Liu, W.-S.; Park, J.; Ellis, C.; Ganguly, S.; Konchar, S.; Cluderay, J.; Leslie, R.; Wilson, S.; Sarau, H. M. Melanin-concentrating hormone is the cognate ligand for the orphan G protein-coupled receptor SLC-1. Nature 1999, 400, 261-265.
24. (b) Saito, Y.; Nothacker, H.-P.; Wang, Z.; Lin, S. H. S.; Leslie, F.; Civelli, O. Molecular characterization of the melanin-concentrating-hormone receptor. Nature 1999, 400, 265-269.
25. Identification of MCH2R: (a) Sailer, A. W.; Sano, H.; Zeng, Z.; McDonald, T. P.; 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.; 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.; Liu, Q. Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7564-7569.
26. (b) An, S.; Cutler, G.; Zhao, J. J.; Huang, S.-G.; Tian, H.; Li, W.; Liang, L.; Rich, M.; Bakleh, A.; Du, J.; Chen, J.-L.; Dai, K. Identification and characterization of a melanin concentrating hormone receptor. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 7576-7581.
27. 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. T.; 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.
28. Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.; Kato, K.; Shimomura, Y.; Mori, M.; Murakoshi, H.; Kato, K.; Suzuki, N.; Nishimura, O.; Fujino, M. T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur. J. Pharmacol. 2002, 438, 129-135.
29. (a) Bednarek, M. A.; Hreniuk, D. L.; Tan, C.; Palyha, O. C.; MacNeil, D. J.; Van der Ploeg, L. H. Y.; Howard, A. D.; Feighner, S. D. Synthesis and biological evaluation in vitro of selective, high affinity peptide antagonists of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1. Biochemistry 2002, 41, 6383-6390.
30. (b) Shearman, L. P.; Camacho, R. E.; Stribling, D. S.; Zhoua, D.; Bednarek, M. A.; Hreniuk, D. L.; Feighner, S. D.; Tan, C. P.; Howard, A. D.; Van der Ploeg, L. H. T.; 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. Note: the peptide sequence for the antagonist (compound B) is erroneous in ref 15b; the correct one is given in ref 15a.
31. (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)-AM1-(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.
32. (b) 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.
33. (a) Receveur, J.-M.; Bjurling, E.; Ulven, T.; Little, P. B.; Nørregaard, P. K.; Högberg, T. 4-Acylamino- and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 5075-5080.
34. (b) Högberg, T.; Bjurling, A. E.; Receveur, J.-M.; Little, P. B.; Elling, C. E.; Nørregaard, P. K.; Ulven, T. Novel methoxybenzamide compounds for use in MCH receptor related disorders. Int. Pat. Appl. WO 03/087045 A1, 2003.
35. (a) The term physicogenetic refers to a method for classifying receptors by comparing physicochemical properties of the binding site amino acid residues and thereby identifying the receptors most likely to bind similar ligands, as opposed to conventional phylogenetic classification comparing homologies of the entire protein sequence.
36. (b) Frimurer, T.; Ulven, T.; Elling, C.; Gerlach, L.-O.; Högberg, T. A physicogenetic method to assign ligand-binding relationships between 7TM receptors applied on CRTH2. Drugs Future 2004, 29 (Suppl. A), 79 (18th International Symposium on Medicinal Chemistry).
37. (c) Frimurer, T. M.; Ulven, T.; Elling, C. E.; Gerlach, L.-O.; Kostenis, E.; Högberg, T. A physicogenetic method to assign ligand-binding relationships between 7TM Receptors. Bioorg. Med. Chem. Lett. 2005, 15, 3707-3712.
38. 2-receptor selective antagonists. Drug Design Discovery 1993, 9, 333-350.
39. 2 antagonist. J. Pharm. Pharmacol. 1987, 39, 787-796.
40. (a) Frimurer, T. M. Unpublished results,
41. (b) Recently a corroborating study on a simulated complex of the aminotetraline T-226296 with MCH1R has been published: Vitale, R. M.; Pedone, C.; De Benedetti, P. G.; Fanelli, F. Structural features of the inactive and active states of the melanin-concentrating hormone receptors: insights from molecular simulations. Proteins 2004, 56, 430-448.
42. Frimurer, T. M.; Ulven, T.; Högberg, T.; Nørregaard, P. K.; Little, P. B.; Receveur, J.-M. Quinoline compounds for use in MCH receptor related disorders. Int. Pat. Appl. WO 04/052370 A2, 2004.
43. (a) Clark, D. E.; Higgs, C.; Wren, S. P.; Dyke, H. J.; Wong, M.; Norman, D.; Lockey, P. M.;. Roach, A. G. A virtual screening approach to finding novel and potent antagonists at the melanin-concentrating hormone 1 receptor. J. Med. Chem. 2004, 47, 3962-3971.
44. (b) Arienzo, R.; Clark, D. E.; Cramp, S.; Daly, S.; Dyke, H. J.; Lockey, P.; Norman, D.; Roach, A. G.; Stuttle, K.; Tomlinson, M.; Wong, M.; Wren, S. P. Structure-activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 4099-4102.
45. (a) Devita, R. J.; Chang, L.; Chaung, D.; Hoang, M.; Jiang, J.; Lin, P.; Sailer, A. W.; Young, J. R. 2-Aminoquinoline compounds. Int. Pat. Appl. WO 03/045313 A2, 2003.
46. (b) Devita, R. J.; Chang, L.; Hoang, M.; Jiang, J.; Lin, P.; Sailer, A. W. 4-Aminoquinoline compounds. Int. Pat. Appl. WO 03/045920 A1, 2003.
47. (a) Souers, A. J.; Wodka, D.; Gao, J.; Lewis, J. C.; Vasudevan, A.; Gentles, R.; Brodjian, S.; Dayton, B.; Ogiela, C. A.; Fry, D.; Hernandez, L. E.; Marsh, K. C.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 1. Bioorg. Med. Chem. Lett. 2004, 14, 4873-4877.
48. (b) Vasudevan, A.; Wodka, D.; Verzal, M. K.; Souers, A. J.; Gao, J.; Brodjian, S.; Fry, D.; Dayton, B.; Marsh, K. C.; Hernandez, L. E.; Ogiela, C. A.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. Bioorg. Med. Chem. Lett. 2004, 14, 4879-4882.
49. (c) Souers, A. J.; Wodka, D.; Gao, J.; Lewis, J. C.; Vasudevan, A.; Brodjian, S.; Dayton, B.; Ogiela, C. A.; Fry, D.; Hernandez, L. E.; Marsh, K. C.; Collins, C. A.; Kym, P. R. Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3. Bioorg. Med. Chem. Lett. 2004, 14, 4883-4886.
50. Catalyst 4.7; Accelrys, Inc. 10188 Telesis Court, Suite 100, San Diego, CA 92121; www.accelrys.com).
51. (a) Frimurer, T. M.; Peters, G. H.; Iversen, L. F.; Andersen, H. S.; Møller, N. P.; Olesen, O. H. Ligand-induced conformational changes: improved predictions of ligand binding conformations and affinities. Biophys. J. 2003, 84, 2273-2281.
52. (b) Stultz, C. M.; Karplus, M. Dynamic ligand design and combinatorial optimization. Proteins: Struct., Funct., Genet. 2000, 40, 258-289.
53. Krahler, S. E.; Burger, A. Cyclic aminoalkylamino derivatives of lepidine. J. Am. Chem. Soc. 1941, 63, 2367-2371.
54. Johnson, O. H.; Hamilton, C. S. Syntheses in the quinoline series. III. The nitration of 2-chloro-4-methylquinoline and the preparation of some 2-hydroxy-4-methyl-8-(dialkylaminoalkyl)-aminoquinolines. J. Am. Chem. Soc. 1941, 63, 2867-2869.
55. (a) Bickerdike, M. J. 5-HT2C receptor agonists as potential drugs for the treatment of obesity. Curr. Top. Med. Chem. 2003, 3, 885-897.
56. (b) Hayashi, A.; Sonoda, R.; Kimura, Y.; Takasu, T.; Suzuki, M.; Sasamata, M.; Miyata, K. Antiobesity effect of YM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res. 2004, 1011, 221-227.
57. a calculations were performed with the on-line calculator SPARC: http://ibmlc2.chem.uga.edu/sparc/.
58. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.
59. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal structure of rhodopsin: A G protein-coupled receptor. Science 2000 289, 739-745.
60. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rogers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. The Protein Data Bank: a computer based archival file for macromolecular structure. J. Mol. Biol. 1997, 112, 535-542.
61. (a) Marti-Renom, M. A.; Stuart, A.; Fiser, A.; Sánchez, R.; Melo, F.; Sali, A. Comparative protein structure modeling of genes and genomes. Annu. Rev. Biophys. Biomol. Struct. 2000, 29, 291-325.
62. (b) Sali, A.; Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 1993, 234, 779-815.
63. Fiser, A.; Do, R. K.; Sali, A. Modeling of loops in protein structures. Protein Sci. 2000, 9, 1753-1773.
64. SYBYL 7.0; Tripos Inc. (1699 South Hanley Road, St. Louis, MO, 63144).
65. Rarey, M.; Kramer, B.; Lengauer, T. Docking of hydrophobic ligands with interaction-based matching algorithms. Bioinformatics 1999, 15, 243-250.
66. (a) Gether, U.; Marray, T.; Schwartz, T. W.; Johansen, T. E. Stable expression of high affinity NK1 (substance P) and NK2 (neurokinin A) receptors but low affinity NK3 (neurokinin B) receptors in transfected CHO cells. FEBS Lett. 1992, 296, 241-244.
67. (b) Johansen, T. E.; Schøller, M. S.; Tolstoy, S.; Schwartz, T. W. Biosynthesis of peptide precursors and protease inhibitors using new constitutive and inducible eukaryotic expression vectors. FEBS Lett. 1990, 267, 289-294.