NPY Y1 and Y5 receptor selective antagonists as anti-obesity drugs

Current Topics in Medicinal Chemistry

Volumn 7, Issue 17, 2007, Pages 1721-1733

  MacNeil, Douglas J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Antagonist; Neuropeptide Y; Obesity; Receptor; Y1; Y5

Indexed keywords

1 NAPHTHALENESULFONIC ACID [4 [(4 AMINO 2 QUINAZOLINYLAMINO)METHYL]CYCLOHEXYLMETHYL]AMIDE; 1,2,3,4 TETRAHYDROCARBAZOLE DERIVATIVE; ANTIOBESITY AGENT; ANTISENSE OLIGONUCLEOTIDE; APPETITE STIMULANT; BENZAZEPINE DERIVATIVE; BMS 193885; DIHYDROPYRIDINE DERIVATIVE; FMS 586; FR 252384; GW 438014A; J 104870; L 152804; LY 357897; MK 0557; N [1 [4 [[[[4 [(DIMETHYLAMINO)METHYL]CYCLOHEXYL]METHYL]AMINO]IMINOMETHYL]BENZYL] 2 OXO 2 (1 PYRROLIDINYL)ETHYL] ALPHA [(2 NAPHTHALENYLSULFONYL)AMINO]BENZENEPROPANAMIDE; N2 DIPHENYLACETYL N (4 UREIDOMETHYLBENZYL)ARGININAMIDE; NALPHA (DIPHENYLACETYL) N (4 HYDROXYBENZYL) DEXTRO ARGININAMIDE; NEUROPEPTIDE Y [34 PROLINE]; NEUROPEPTIDE Y RECEPTOR; NEUROPEPTIDE Y RECEPTOR ANTAGONIST; NEUROPEPTIDE Y1 RECEPTOR ANTAGONIST; NEUROPEPTIDE Y5 RECEPTOR ANTAGONIST; NEUROPEPTIDE Y5 RECEPTOR ANTAGONIST 972; NEUROPEPTIDE Y[31 LEUCINE 34 PROLINE]; PD 160170; PEPTIDE YY; PLACEBO; S 25585; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ABSENCE OF SIDE EFFECTS; BINDING AFFINITY; CLINICAL TRIAL; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG PENETRATION; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; FOOD INTAKE; HOMEOSTASIS; HUMAN; NONHUMAN; OBESITY; PROTEIN FUNCTION; REVIEW; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-OBESITY AGENTS; HUMANS; OBESITY; RECEPTORS, NEUROPEPTIDE Y;

EID: 36248946214     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802607782341028     Document Type: Review

References (128)

1. Mokdad, A. H.; Ford, E. S.; Bowman, B. A,; Dietz, W. H.; Vinicor, F.; Bales, V. S.; Marks, J. S. Prevalence of obesity, diabetes, and obesity related health risk factors. J. Amer. Med. Assoc. 2003, 289, 76-79.
2. Stanley, B.G.; Leibowitz, S.F. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc. Nat. Acad Sci.(USA) 1985, 82, 3940-3943.
3. Stanley, B.G.; Magdalin, W.; Seirafi, A.; Nguyen, M.M.; Leibowitz, S.F. Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect. Peptides 1992, 13, 581-587.
4. Akabayashi, A.; Wahlestedt, C.; Alexander, J.T; Leibowitz, S.F. Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion. Brain Res. Mol. Brain Res. 1994, 21, 55-61.
5. Dube, M.G.; Xu, B.; Crowley, W.R.; Kalra, S.P.; Kalra, P.S. Evidence that neuropeptide Y is a physiological signal for normal food intake. Brain Res. 1994, 646, 341-344.
6. Stanley, B.G.; Kyrkouli, S.E.; Lampert, S.; Leibowitz, S. F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 1986, 7, 1189-92.
7. Raposinho, P.D.; Pedrazzini, T.; White, R.B.; Palmiter, R.D.; Aubert, M.L. Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression. Endocrinology 2004, 145, 304-310.
8. Raposinho, P.D.; Pierroz, D.D.; Broqua, P.; White, R.B.; Pedrazzini, T.; Aubget, M.L. Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism. Mol. Cell. Endocrinol. 2001, 185, 195-204.
9. Beck, B.; Strioker-Krongrad, A.; Nicolas, J., Burlet, C. Chronic and continuous intracerebroventricular infusion of neuropeptide Y in Long Evans rats mimics the feeding behaviour of obese Zucker rats. Int. J. Obes. Relat. Metab. Disord. 1992, 16, 295-302.
10. Brown, C.M.; Coscina, D.V.; Fletcher, P.J. The rewarding properfies of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens. Peptides 2000, 21, 1279-1297.
11. Brown, C.M.; Fletcher, P.J.; Coscina, D.V. Neuropeptide Y induced operant responding for sucrose is not mediated by dopamine. Peptides 1998, 19, 1667-1673.
12. Flood, J.F.; Morley, J.E. Increased food intake by neuropeptide Y is due to an increased motivation to eat. Peptides 1991, 12, 1329-1332.
13. Zimany, I.A.; Fathi, Z.; Poindexter, G. Central control of feeding behavior by neuropeptide Y. Curr. Pharm. Des. 1998, 4, 349-366.
14. Serradeil-Le Gal, C.; Lafontan, M.; Raufaste, D.; Marchand, J.; Pouzet, B.; Casellas, P.; Pascal, M.; Maffrand, J.P.; Le Fur, G. Characterization of NPY receptors controlling lipolysis and leptin secretion in human adipocytes. FEBS Lett. 2000, 475, 150-6.
15. Larsen, P. J.; Tang-Christensen, M.; Stidsen, C.E.; Madsen, K.; Smith, M. S.; Cameron, J. L.; Activation of central neuropeptide Y Y1 receptors potently stimulates food intake in male rhesus monkeys. J. Clin. Endocrinol. Metab. 1999, 84, 3781-3791.
16. Erickson, J.C.; Clegg, K.E.; Palmiter, R.D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996, 381, 415-421,
17. Segal-Lieberman, G.; Trombly, D.J.; Juthani, V.; Wang, X.; Maratos-Flier, E. NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E1131-1139.
18. Qian, S.; Chen, H.; Weingarth, D.; Trumbauer, M.E.; Novi, D.E.; Guan, X; Yu, H.; Shen, Z.; Feng, Y.; Frazier, E. Chen, A.; Camacho, R.E.; Shearman, L.P.; Gopal-Truter, S.; MacNeil, D.J.; Van der Ploeg, L.H.; Marsh, D.J. Neither agouti related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol. Cell. Biol. 2002, 22, 5027-5035.
19. Hohmann, J.G.; Teklemichael, D.N.; Weinshenker, D.; Wynick, D.; Clifton, D.K.; Steiner, R.A. Obesity and endocrine dysfunction in mice with deletions of both neuropeptide Y and galanin. Mol. Cell. Biol. 2004, 24, 2978-2985.
20. Erickson, J.C.; Hollopeter, G.; Palmiter, R.D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 1996, 274, 1704-1707.
21. Gardiner, J. V.; Kong, W. M.; Ward, H.; Murphy, K. G.; Dhillo, W. S.; Bloom, S. R.. AAV mediated expression of anti-sense neuropeptide Y cRNA in the arcuate nucleus of rats results in decreased weight gain and food intake. Biochem Biophys Res Commun. 2005, 327, 1088-1093.
22. Gropp, E.; Shanabrough, M.; Borok, E.; Xu A.W.; Janoschek, R.; Buch, T.; Plum, L.; Balthasar, N.; Hampel, B.; Waisman, A.; Barsh, G.S.; Horvath, T.L.; Bruning, J.C. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci. 2005, 8, 1289-2191.
23. Bewick, G. A.; Gardiner, J. V.; Dhillo, W. S.; Kent, A.S.; White, N. E.; Webster, Z.; Ghatei, M. A.; Bloom, S. R. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 2005, 19, 1680-1682.
24. Luquet, S.; Perez, F.A.; Hnasko, T.S.; Palmiter, R.D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 2005, 310, 683-685.
25. Berglund, M.; Hipskind, P.; Gehlert, D. R. Recent developments in our understanding of the physiological role of PP fold peptide receptor subtypes. Exp. Biol. Med. 2003, 228, 217-44.
26. NPY family of peptides in neurobiology, cardiovascular and metabolic disorders; from genes to therapeutics; Zukowska, Z.; Feuerstein, G. Birkhauser Verlag, Berlin. 2006.
27. Eva, C.; Serra, M.; Mele, P.; Panzica, G.; Oberto, A. Physiology and gene regulation of the brain NPY Y1 receptor. Front Neuroendocrinol. 2006, 27, 308-339.
28. Erondu, N.; Gantz, I.; Musser, B.; Suryawanshi, S.; Mallick, M.; Addy, C.; Cote, J.; Bray, G.; Fujioka, K.; Bays, H.; Hollander, P.; Sanabria-Bohorquez, S. M.; Eng, W.; Langstrom, B.; Hargreaves, R. J.; Burns, H. D.; Kanatani, A.; Fukami, T.; MacNeil, D. J.; Gottesdiener, K. M.; Amatruda, J. M.; Kaufman, K. D.; Heymsfield, S. B. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Cell. Metab. 2006, 4, 275-282.
29. Ishihara, A.; Moriya, M.; MacNeil, D. J.; Fukami, T.; Kanatani, A. Neuropeptide Y receptors as targets of obesity treatment. Expert Opin. Therap. Patents 2006, 16, 1701-1712.
30. Gerald, C.; Walker, M.W.; Criscione, L.; Gustafson, E.L.; Batzl-Hartmann, C.; Smith, K.E.; Vaysse, P.; Durkin, M.M.; Laz, T.M.; Linemeyer, D.L.; Schaffhauser, A.O.; Whitebread, S.; Hofbauer, K.G.; Taber, R.I.; Branchek, T.A.; Weinshank, R.L. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 1996, 382, 168-171.
31. Chamorro, S,; Della-Zuana, O.; Fauchere, J.L.; Feletou, M.; Galizzi, J.P.; Levens, N. Appetite suppression based on selective inhibition of NPY receptors. Int. J. Obes. Relat. Metab. Disord. 2002, 26, 281-298.
32. Kanatani, A.; Ishihara, A.; Iwaasa, H.; MacNeil, D.J.; Fukami, T. Development of NPY antagonists and their anorectic effects. Folia Pharmacologica Japonica 2006, 127, 88-91.
33. Levens, N.R.; Della-Zuana, O. Neuropeptide Y Y5 receptor antagonists as anti-obesity drugs. Curr. Opin. Investig. Drugs 2003, 4, 1198-1204.
34. Henry, M.; Ghibaudi, L.; Gao, L.; Hwa, J.J. Energy metabolic profile of mice after chronic activation of central NPY Y1, Y2, or Y5 receptors. Obes. Res. 2005, 13, 36-47.
35. Kanatani, A.; Mashiko, S.; Murai, N.; Sugimoto, N.; Ito, J.; Fukuroda, T.; Fukami, T.; Morin, N.; MacNeil, D.J.; Van der Ploeg, LH.; Saga, Y.; Nishimura, S.; Ihara, M. Role of Y1 receptor in the regulation of neuropeptide Y mediated feeding: comparison of wild type, Y1 receptor deficient, and Y5 receptor deficient mice. Endocrinology 2000, 141, 1014-1016.
36. Haynes, A.C.; Arch, J.R.; Wilson, S,; McClue, S.; Buckingham, R.E. Characterization of the neuropeptide Y receptor that mediates feeding in the rat: a role for the Y5 receptor? Regul. Pept. 1998, 75-76, 355-361.
37. Wyss, P.; Stricker-Krongrad, A.; Brunner, L.; Miller, J.; Crossthwaite, A.; Whitebread, S.; Criscione, L The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes. Regul. Pept. 1998, 75-76, 363-371.
38. Borowsky, B.; Walker, M.W.; Bard, J.; Weinshank, R.L.; Laz, T.M.; Vaysse, P.; Branchek, T.A,; Gerald, C. Molecular biology and pharmacology of multiple NPY Y5 reteptor species homologs. Regul. Pept. 1999, 25, 45-53.
39. Larsen, P. J.; Sheikh, S. P.; Jakobsen, C. R.; SchwartzI T. W.; Mikkelsen, J. D. Regional distribution of putative NPY Y1 receptors and neurons expressing Y1 mRNA in forebrain areas of the rat central nervous system. Eur. J. Neurosci. 1993, 5, 1622-1637.
40. Corp, E.S.; McQuade, J.; Krasnicki, S.; Conze, D.B. Feeding after fourth ventricular administration of neuropeptide Y receptor agonists in rats. Peptides 2001, 22, 493-499.
41. Mullins, D.; Kirby, D.; Hwa, J.; Guzzi, M.; Rivier, J.; Parker, E. Identification of potent and selective neuropeptide Y Y1 receptor agonists with orexigenic activity in vivo. Mol. Pharmacol. 2001, 60, 534-540.
42. Lecklin, A,; Lundell, I.; Salmela, S.; Mannisto, P.T.; Beck-Sickinger, A.G.; Larhammar, D. Agonists for neuropeptide Y receptors Y1 and Y5 stimulate different phases of feeding in guinea pigs. Br. J. Pharmacol. 2003, 139, 1433-1440.
43. Pedrazzini, T.; Seydoux, J. F.; Kunstner, P.; Aubert, J.; Grouzmann, E.; Beermann, F.; Bruimer, H. R. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat. Med. 1998, 46, 722-726.
44. Kushi, A.; Sasai, H.; Koizumi, H.; Takeda, N.; Yokoyama, M.; Nakamura, M. Obesity and mild hyperinsulinemia found in neuropeptide Y Y1 receptor deficient mice. Proc. Nat. Acad. Sci.(USA) 1998, 95, 15659-15664.
45. Pralong, F.P.; Gonzales, C.; Voirol, M.J.; Palmiter, R.D.; Brunner, H.R.; Gaillard, R.C.; Seydoux, J.; Pedrazzini, T. The neuropeptide Y Y1 receptor regulates leptin mediated control of energy homeostasis and reproductive functions. FASEB J. 2002, 16, 712-714.
46. Heilig, M. Antisense inhibition of neuropeptide Y (NPY)-Y1 receptor expression blocks the anxiolytic-like action of NPY in amygdala and paradoxically increases feeding. Regul. Pept. 1995, 59, 201-265.
47. Lopez-Valpuesta, F. J.; Nyce, Y. W.; Myers; R. D. NPY-Y1 receptor antisense injected centrally in rats causes hyperthermia and feeding. Neuroreport. 1996, 7, 2781-2784.
48. Schaffhauser, A. O.; Whitebread, S.; Haener, R., Hofbauer, K. G.; Stricker-Krongrad, A. Neuropeptide Y Y1 receptor antisense oligodeoxynucleotides enhance food intake in energy-deprived rats. Regul. Pept. 1998, 75-76, 417-423.
49. Lopez-Valpuesta, F. J.; Nyce, J. W.; Griffin-Biggs, T. A.; Ice, J.C.; Myers, R. D. Antisense th NPY-Y1 demonstrates that Y1 receptors in the hypothalamus underlie NPY hypothermia and feeding in rats. Proc. Biol. Sci. 1996, 263, 881-886.
50. Doods, H.N.; Wieland, H.A.; Engel, W.; Eberlein, W.; Willim, K.D.; Entzeroth. M.; Wienen, W.; Rudolf, K. BIBP 3226, the first selective neuropeptide Y1 receptor antagonist: a review of its pharmacological properties. Regul. Pept. 1996, 65, 71-77.
51. Kask, A, Rago, L, Harro, J. Evidence for involvement of neuropeptide Y receptors in the regulation of food intake: studies with Y1-selective antagonist BIBP 3226. Br. J. Pharmacol. 1998, 124, 1507-1515.
52. Morgan, D.G.; Small, C.J.; Abusnana, S.; Turton, M.; Gunn, L; Heath, M.; Rossi, M.; Goldstone, A.P.; O'Shea, D.; Meeran, K.; Ghatei, M.; Smith, D. M.; Bloom S. The NPY Y1 receptor antagonist BIBP 3226 blocks NPY induced feeding via a non-specific mechanism. Regul. Pept. 1998, 75-76, 377-382.
53. Wieland, H. A.; Engel, W.; Eberlein, W.; Rudolf, K.;, Doods, H. N. Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Br. J. Pharmacol. 1998, 125, 549-555.
54. Malmstrom, R. E.; Alexandersson, A.; Balmer, K. C.; Weilitz, J. In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H 409/22. J. Cardiovasc. Pharmacol. 2000, 36, 516-525.
55. Kanatani, A. Ishihara, A.; Asahi, S.; Tanaka, T.; Ozaki, S.; Ihara, M.; Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake. Endocrinology 1996, 137, 3177-3182.
56. Serradeil-Le Gal, C., Valette, G.; Rouby, P.-E.; Pellet, A.; Oury-Donat, F.; Brossard, G.; Lespy, L,; Marty, E.; Neliat, G.; de Cointet P.; Maffrand, J.-P.; Le Fur, G. SR120819A, an orally-active and selective neuropeptide Y Y1 receptor antagonist. FEBS Lett. 1995, 362, 192-196.
57. Wright, J.; Bolton, G.; Creswell, M.; Downing, D.; Georgic, L.; Heffner, T.; Hodges, J.; MacKenzie, R.; Wise, L. 8-amino-6-(arylsulphonyl)-5-nitroquinolines: novel nonpeptide neuropeptide Y1 receptor antagonists. Bioorg. Med. Chem. Lett. 1996, 6, 1809-1814.
58. Zimmerman, D. M.; Cantrell, B. E.; Smith, E. C.; Nixon, J. A.; Bruns, R. F.; Gitter, B.; Hipskind, P, A.; Ornstein, P. L.; Zarrinmayeh, H.; Britton, T. C.; Schober, D. A.; Gehlert, D. R. Structure-activity relationships of a series of 1-substitated-4-methylbenzimidazole neuropeptide Y-1 receptor antagonists. Bioorg. Med. Chem. Lett. 1998, 8, 473-476.
59. Zarrinmayeh, H.; Nunes, A. M.; Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.; Schober, D. A.; Gackenheimer, S. L.; Bruns, R. F.; Hipskind, P. A.; Britton, T. C.; Cantrell, B. E.; Gehlert, D. R Synthesis and evaluation of a series of novel 2-[(4-chlorophenoxy) methylbenzimidazoles as selective neuropeptide Y Y1 receptor antagonists. J. Med. Chem. 1998, 41, 2709-2719.
60. Zarrinmayeh, H.; Zimmerman, D. M.; Cantrell, B. E.; Schober, D. A.; Bruns, R.F.; Gackenheimer, S. L.; Ornstein, P. L.; Hipskind, P. A.; Britton, T.C.; Gehlert, D. R. Structure-activity relationship of a series of diaminoalkyl substituted benzimidazole as neuropeptide Y Y1 receptor antagonists. Bioorg. Med. Chem. Lett. 1999, 9, 647-652.
61. Britton, T.C.; Spinazze, P. G.; Hipskind, P. A.; Zimmerman, D. M.; Zarrinmayeh, H.; Schober, D. A.; Gehlert, D. R,; Bruns, R.F. Structure-activity relationships of a series of benzothiophene-derived NPY Y1 antagonists: optimization of the C-2 side chain. Bioorg Med. Chem. Lett. 1999, 9, 475-480.
62. Hipskind, P. A.; Lobb, K. L.; Nixon, J. A.; Britton, T. C.; Bruns, R.F.; Catlow, J.; Dieckman-McGinty, D. K.; Gackenheimer, S. L.; Gitter, B. D.; Iyengar, S.; Schober, D. A.; Simmons, R. M.; Swanson, S.; Zarrinmayeh, H.; Zimmerman, D. M.; Gehlert, D. R. Potent and selective 1,2,3-trisubstituted indole NPY Y-1 antagonists. J. Med. Chem. 1997, 40, 3712-3714.
63. Poindexter G. S.; Bruce, M. A. LeBoulluec, K. L.; Monkovic, I.; Martin, S.. W.; Parker, E.M.; Iben, L. G.; McGovern, R. T.; Ortiz, A. A.; Stanley, J. A. Mattson, G. K.; Kozlowski, M.; Arcuri, M.; Antal-Zimanyi, I. Dibydropyridine neuropeptide Y Y(1) receptor antagonists. Bioong. Med. Chem. Lett. 2002, 12, 379-382.
64. Sit, S. Y.; Huang, Y.; Antal-Zimanyi, I.; Ward, S.; Poindexter, G.S. Novel dihydropyrazine analogues as NPY antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 337-340.
65. Luo, G. Mattson, G. K.; Bruce, M. A.; Wong, H.; Murphy, B. J.; Longhi, D.; Antal-Zimanyi, I.; Poindexter, G. S. Isosteric N-arylpiperazine replacements in a series of dihydropyridine NPY1 receptor antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 5975-5978.
66. Poindexter, G. S.; Bruce, M. A.; Breitenbucher, J. G.; Higgins, M. A.; Sit, S. Y.; Romine, J. L.; Martin, S. W.; Ward, S. A.; McGovern, R. T.; Clarke, W.; Russell, J.; Antal-Zimanyi, I. Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements. Bioorg. Med. Chem. 2004, 12, 507-521.
67. Murakami, Y.; Hagishita, S.; Okada, T.; Kii, M.; Hashizume, H.; Yagami, T.; Fujimoto, M. 1,3-Disubstituted benzazepines A neuropeptide Y Y1 receptor antagonists. Bioorg. Med. Chem. 1999, 7, 1703-1714.
68. Murakami, Y.; Hara, H.; Okada, T.; Hashizume, H.; Kii, M;; Ishihara, Y.; Ishikawa, M.; Shimamura, M.; Mihara, S.; Kato, G.; Hanasaki, K.; Hagishita, S.; Fujimoto, M. 1,3-Disubstittited benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists. J. Med. Chem. 1999, 42, 2621-2632.
69. Di Fabio, R.; Giovannini, R.; Bertani, B.; Borriello, M.; Bozzoli, A.; Donati, D.; Falchi,A.; Ghirlanda, D.; Leslie, C. P.; Pecunioso, A.; Rumboldt, G.; Spada, S.; Synthesis and SAR of substituted tetrahydrocarbazole derivatives as new, NPY-1 antagonists. Bioorg. Med. Chem. Lett. 2006, 16, 1749-1752.
70. Sato, N.; Shibata, T.; Jitsuoka, M.; Ohno, T.; Takahashi, T.; Hirohashi, T.; Kanno, T.; Iwaasa, H.; Kanatani, A.; Fukami, T. Synthesis and evaluation of substituted 4-alkoxy-2-aminopyridines 4 novel neuropeptide Y1 receptor antagonists. Bioorg. Med. Chem. Lett. 2004 14, 1761-1764.
71. Kanatani, A.; Kanno, T.; Ishihara, A.; Hata, M.; Sakuraba, A.; Tanaka, T.; Tsuchiya, Y.; Mase, T.; Fukuroda, T.; Fukami, T.; Ihara, M. The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability. Biochem. Biophys. Res. Commun. 1999, 266, 88-91.
72. Kanatani, A.; Hata, M.; Mashiko, S.; Ishihara, A,; Okamoto, O.; Haga, Y.; Ohe, T.; Kanno, T.; Murai, N.; Ishii, Y.; Fukuroda, T.; Fukami, T.; Ihara, M. A typical Y1 receptor regulates feeding behaviors: effects of a potent and selective Y1 antagonist, J-115814. Mol. Pharmacol. 2001, 59, 501-505.
73. Ishihara, A.; Kanatani, A.; Okada, M.; Hidaka, M.; Tanaka, T.; Mashiko, S.; Gomori, A.; Kanno, T.; Hata, M.; Kanesaka, M.; Tominaga, Y.; Sato, N. A.; Kobayashi, M.; Murai, T.; Watanabe, K.; Ishii, Y.; Fukuroda, T.; Fukami, T.; Ihara, M. Blockade of body weight gain and plasma corticosterone levels in Zucker fatty rats using an orally active neuropeptide Y Y1 antagonist. Br. J. Pharmacol. 2002, 136, 341-346.
74. Della-Zuana, O.; Revereault, L.; Beek-Sickinger, A.; Monge, A.; Caignard, D. H.; Fauchere, J. L.; Henlin, J. M.; Audinot, V.; Boutin, J. A.; Chamorro, S.; Feletou, M.; Levens, N. A potent and selective NPY Y5 antagonist reduces food intake but not through blockade of the NPY Y5 receptor. Int. J. Obes. Relat. Metab. Disord. 2004, 28:628-639.
75. McCrea, K.; Wisialowski, T.; Cabrele, C.; Church, B.; Beck-Sickinger, A.; Kraegen, E.; Herzog, H. 2-36[K4,RYYSA(19-23)]PP a novel Y5-receptor preferring ligand with strong stimulatory effect on food intake. Regul. Pept. 2000, 87, 47-58.
76. Parker, E. M.; Balasubramaniam, A.; Guzzi, M.; Mullins, D. E.; Salisbury, B. G.; Sheriff, S.; Witten, M. B.; Hwa, J. J. [D-Trp(34)] neuropeptide Y is a potent and selective neuropeptide Y Y(5) receptor agonist with dramatic effects on food intake. Peptides 2000, 21, 393-939.
77. Cabrele, C.; Langer, M.; Bader, R.; Wieland, H. A.; Doods, H. N.; Zerbe, O.; Beck-Sickinger, A. G. The first selective agonist for the neuropeptide YY5 receptor increases food intake in rats. J. Biol. Chem. 2000, 275, 36043-36048.
78. Hwa, J. J.; Witten, M. B.; Williams, P.; Ghibaudi, L.; Gao, J.; Salisbury, B. G.; Mullins, D. Hamud, F.; Strader, C. D.; Parker, E. M. Activation of the NPY Y5 receptor regulates both feeding and energy expenditure. Am. J. Physiol. 2000, 277, R1428-R1434.
79. Mashiko, S., Ishihara, A.; Iwaasa, H.; Sano, H.; Oda, Z.; Ito, J.; Yumoto, M.; Okawa, M.;. Suzuki, J.; Fukuroda, T.; Jitsuoka, M.; Morin, N.; MacNeil, D. J.; Van der Ploeg, L. H.; Ihara, M.; Fukami, T.; Kanatani, A. Characterization of neuropeptide Y (NPY) Y5 receptor mediated obesity in mice:chronic intrecerebroventrioular infusion of D Trp34NPY. Endocrinology 2003, 144, 1793-1801.
80. Fekete, C.; Sarkar, S.; Rand, W. M.; Harney, J, W.; Emerson, C. H.; Bianco, A. C.; Beck-Sickinger, A.; Lechan, R. M. Neuropeptide Y1 and Y5 receptors mediate the effects of neuropeptide. Y on the hypothalamic-pituitary-thyroid axis. Endocrinology 2002, 143, 4513-4519.
81. Marsh, D.J.; Hollopeter, G.; Kafer, K. E.; Palmiter, R. D.; Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat. Med. 1998, 4, 718-721.
82. Schaffhauser, A. O.; Stricker-Krongrad, A,; Hofbauer, K. G. NPY Y5 receptor subtype. Pharmacological characterization with antisense oligodeoxynucleotide screening strategy. Methods Mol. Biol. 2000, 153, 129-150.
83. Tang-Christensen, M.; Kristensen, P.; Stidsen, C. E.; Brand, C. L.; Larsen, P. J. Central administration of Y5 receptor antisense decreases spontaneous food intake and attenuates feeding in response to exogenous neuropeptide Y. J. Endocrinol. 1998, 159, 307-312.
84. Flynn, M. C.; Turrin, N. P.; Plata-Salaman, C. R.; Ffrench-Mullen, J. M. Feeding response to neuropeptide Y-related compounds in rats treated with Y5 receptor antisense or sense phosphothio-oligodeoxynucleotide. Physiol. Behav. 1999, 66, 881-884.
85. Gong, H. X.; Guo, X. R.; Fei, L.; Guo, M.; Liu, Q. Q.; Chen, R. H. Lipolysis and apoptosis of adipocytes induced by neuropeptide Y-Y5 receptor antisense oligodeoxynucleotides in obese rats. Acta Pharmacol. Sin. 2003, 24, 569-575.
86. Dryden, S.; Pickavance, L.; Tidd, D.; Williams, G. The lack of specificity of neuropeptide Y (NPY) antisense oligodeoxy-nucleotides administered intracerebroventricularly in inhibiting food intake and NPY gene expression in the rat hypothalamus. J. Endocrinol. 1998, 157, 169-175.
87. Larhammar, D.; Salaneck, E. Molecular evolution of NPY receptor subtypes. Neuropeptides 2004, 8, 141-151.
88. Criscione, L.; Rigollier, P.; Batzl-Hartmann, C.; Rueger, H.; Stricker-Krongrad, A.; Wyss, P.; Brunner, L.; Whitebread, S.; Yamaguchi, Y.; Gerald, C.; Heurich, R. O.; Walker, M. W.; Chiesi, M.; Schilling, W.; Hofbauer, K. G.; Levens, N. Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J. Clin. Invest. 1998, 102, 2136-2145.
89. Rueeger, H.; Rigollier, P.; Yamaguchi, Y.; Schmidlin, T.; Schilling, W.; Criscione, L.; Whitebread, S.; Chiesi, M.; Walker, M. W.; Dhanoa, D.; Islam, I.; Zhang, J.; Gluchowski, C. Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 1175-1179.
90. Finn, J.; Pelham, D.; Walker, M. W.; Gluchowski, C. High-throughput synthesis optimization of sulfonamide NPY Y5 antagonists. Bioorg. Med. Chem. Lett. 2000, 8, 1771-1774.
91. Islam, I.; Dhanoa, D.; Finn, J.; Du, P.; Walker, M. W.; Salon, J. A.; Zhang, J.; Gluchowski, C. Discovery of potent and selective small molecule NPY Y5 receptor antagonists. Bioorg. Med. Chem. Lett. 2002, 12, 1767-1769.
92. Galiano, S.; Erviti, O.; Perez, S.; Moreno, A.; Juanenea, L.; Aldana, I.; Monge, A. Synthesis of new thiophene and benzo[b]thiophene hydrazide derivatives as human NPY Y(5) antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 597-599.
93. Moreno, A,; Perez, S.; Galiano, S.; Juanenea, L.; Erviti, O.; Frigola, C.; Aldana, I.; Monge, A. Synthesis and evaluation of new arylsulfonamidomethylcyclohexyl derivatives as human neuropeptide Y Y5 receptor antagonists for the treatment of obesity. Eur. J. Med. Chem. 2004, 39, 49-58.
94. Juanenea, L,; Galiano, S.; Erviti, O.; Moreno, A.; Perez, S.; Aldana, I.; Monge, A. Synthesis and evaluation of new hydrazide derivatives as neuropeptide Y Y5 receptor antagonists for the treatment of obesity. Bioorg. Med. Chem. 2004, 12, 4717-4723.
95. Galiano, S.; Erviti, O.; Perez, S;; Moreno, A.; Juanenea, L.; Aldana, I.; Monge, A. Novel human neuropeptide Y Y5 receptor antagonists for the treatment of obesity. Synthesis and biological evaluation of pyridine hydrazide derivatives. Arzneimittelforschung 2005, 55, 81-85.
96. Kordik, C. P.; Luo, C.; Zanoni, B. C.; Dax, S. L.; McNally, J. J.; Lovenberg, T. W.; Wilson, S. J.; Reitz, A.B. Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor. Bioorg. Med. Chem. Lett. 2001, 11, 2283-2286.
97. McNally, J. J.; Youngman, M. A.; Lovenberg, T. W.; Nepomuceno, D.; Wilson, S.; Dax, S. L. N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: potent antagonists of human neuropeptide Y Y5 receptor. Bioorg. Med. Chem Lett. 2000, 10, 213-216.
98. McNally, J. J.; Youngman, M. A.; Lovenberg, T. W.; Nepomuceno, D.; Wilson, S.; Dax, S. L. N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagoinists of the human neuropeptide Y Y5 receptor. Bioorg. Med. Chem. Lett. 2000, 10, 1641-1643.
99. Youngman, M. A.; McNally, J. J.; Lovenberg, T. W.; Reitz, A. B.; Willard, N. M.; Nepomuceno, D. H.; Wilson, S. J.; Crooke, J. J,; Rosenthal, D.; Vaidya, A. H.; Dax, S. L alpha-Substituted N-(sulfonamido)alkyl-beta-aminotetralins: potent and selective neuropeptide Y Y5 receptor antagonists. J. Med. Chem. 2000, 43, 346-350.
100. Block, M. H.; Boyer S.; Brailsford, W.; Brittain, D. R.; Carroll, D.; Chapman, S.; Clarke, D. S.; Donald, C. S.; Foot,e K. M.; Godfrey, L.; Ladner, A.; Marsham, P. R.; Masters, D. J.; Mee, C. D.; O'Donovan, M. R.; Pease, J. E.; Pickup, A. G.; Rayner, J. W.; Roberts, A.; Schofield, P.; Suleman, A.; Turnbull, A. V. Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity. J. Med. Chem. 2002, 45, 3509-3523.
101. Turnbull, A. V.; Ellershaw, L.; Masters, D. J.; Birtles, S.; Boyer, S.; Carroll, D.; Clarkson, P.; Loxham, S. J.; McAulay, P.; Teague, J. L.; Foote, K. M.; Pease, J. E.; Block, M. H. Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats. Diabetes 2002, 51, 2441-2449.
102. Hammond, M.; Elliott, R. L.; Gillaspy, M. L.; Hager, D. C.; Hank, R. F.; LaFlamme, J. A.; Oliver, R. M.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C. M.; Cassella, J. V. Structure-activity relationships in a series of NPY Y5 antagonists: 3-amido-9-ethylcarbazoles, core-modified analogues and amide isosteres. Bioorg. Med. Chem. Lett. 2003, 13, 1989-1992.
103. Kakui, N.; Tanaka, J.; Tabata, Y.; Asai, K.; Masuda, N.; Miyara, T.; Nakatani, Y.; Ohsawa, F.; Nishikawa, N.; Sugai, M.; Suzuki, M.; Aoki, K.; Kitaguchi, H. Pharmacological characterization and feeding-suppressive property of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1- (2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel, selective, and orally active antagonist for neuropeptide Y Y5 receptor. J. Pharmaco. Exp. Ther. 2006, 317, 562-570.
104. Elliott, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M. L.; Hammond, M.; Hank, R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C. M.; Cassella, J. V. Structure-activity relationship studies on 2-heteroaryl-4-arylimidazoles NPY5 receptor antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 3593-3596.
105. Elliott, R. L.; Oliver, R. M.; Hammond, M.; Patterson, T. A.; She, L.; Hargrove, D. M.; Martin, K. A.; Maurer, T. S.; Kalvass, J. C.; Morgan, B. P.; DaSilva-Jardine, P. A.; Stevenson, R. W.; Mack, C. M.; Cassella, J. V. In vitro and in vivo characterization of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt, a potent and selective NPY5 receptor antagonist. J. Med. Chem. 2003, 46, 670-673.
106. Rueeger, H.; Gerspacher, M.; Buehlmayer, P.; Rigollier, P.; Yamaguchi, Y.; Schmidlin, T.; Whitebread, S.; Nuesslein-Hildesheim, B.; Nick, H.; Cricione, L. Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo [e]azulen derivatives as neuropeptide Y Y5 receptor antagonists. Bioorg. Med. Chem. Lett. 2004, 14, 2451-2457.
107. Tabuchi, S.; Itani, H.; Sakata, Y.; Oohashi, H.; Satoh, Y. Novel potent antagonists of human neuropeptide Y Y5 receptor. Part 1: 2-oxobenzothiazolin-3-acetic acid derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 1171-1175.
108. Itani, H.; Ito, H.; Sakata, Y.; Hatakeyama, Y.; Oohashi, H.; Satoh, Y. Novel potent antagonists of human-neuropeptide Y Y5 receptors. Part 3: 7-methoxy-1-hydroxy-1-substituted tetraline derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 799-802.
109. Itani, H.; Ito, H.; Sakata, Y.; Hatakeyama, Y.; Oohashi, H.; Satoh, Y. Novel potent antagonists of human neuropeptide Y Y5 receptors. Part 2: substituted benzo[a]cycloheptene derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 757-761.
110. Satoh, Y.; Hatori, C.; Ito, H. Novel potent antagonists of human neuropeptide Y-Y5 receptor. Part 4: tetrahydrodiazabenzazulene derivatives. Bioorg. Med. Chem. Lett. 2002, 12, 1009-1011.
111. Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale C.; Han, N.; Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.; Santora, V. J.; Sonnenberg, J. D.; Karbon, W. Structure-activity relationships of a series of pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists. J. Med. Chem. 2000, 43, 4288-3412.
112. Fotsch, C.; Sonnenberg, J. D.; Chen, N.; Hale, C.; Karbon, W.; Norman, M. H. Synthesis and structure-activity relationships of trisubstituted phenyl urea derivatives as neuropeptide Y5 receptor antagonists. J. Med. Chem. 2001, 44, 2344-2356.
113. Sato, N.; Takahashi, T.; Shibata, T.; Haga, Y.; Sakuraba, A.; Hirose, M.; Sato, M.; Nonoshita, K.; Koike, Y.; Kitazawa, H.; Fujino, N.; Ishii, Y.; Ishihara, A.; Kanatani, A.; Fukami, T. Design and synthesis of the potent, orally available, brain-penetrable arylpyrazole class of neuropeptide Y5 receptor antagonists. J. Med. Chem. 2003, 46, 666-669.
114. Takahashi, T.; Sakuraba, A.; Hirohashi, T.; Shibata, T.; Hirose, M.; Haga, Y.; Nonoshita, K.; Kanno, T.; Ito, J.; Iwaasa, H.; Kanatani, A.; Fukami, T.; Sato, N. Novel potent neuropeptide Y Y5 receptor antagonists: synthesis and structure-activity relationships of phenylpiperazine derivatives. Bioorg. Med. Chem. 2006, 14, 7501-7511.
115. Aquino, C. J.; Ramanjulu, J. M.; Heyer, D.; Daniels, A. J.; Palazzo, F.; Dezube, M. Synthesis and structure activity relationship of guanidines as NPY Y5 antagonists. Bioorg. Med. Chem. 2004, 12, 2691-2708.
116. Dordal, A.; Lipkin, M.; Macritchie, J.; Mas, J.; Port, A.; Rose, S.; Salgado, L.; Savic, V.; Schmidt, W.; Serafini, M. T.; Spearing, W.; Torrens, A.; Yeste, S.A preliminary study of the metabolic stability of a series of benzoxazinone derivatives as potent neuropeptide Y5 antagonists. Bioorg. Med. Chem. Lett. 2005, 15, 3679-3684.
117. Torrens, A.; Mas, J.; Port, A.; Castrillo, J.A.; Sanfeliu, O.; Guitart, X.; Dordal, A.; Romero, G.; Fisas, M. A. Sanchez, E.; Hernandez, E.; Perez, P.; Perez, R.; Buschmann, H. Synthesis of new benzoxazinone derivatives as neuropeptide Y5 antagonists for the treatment of obesity. J. Med. Chem. 2005, 48, 2080-2092.
118. Gillman, K. W.; Higgins, M. A.; Poindexter, G. S.; Browning, M.; Clarke, W. J.; Flowers, S.; Grace, J. E. Jr.; Hogan, J. B.; McGovern, R, T.; Iben, L. G.; Mattson, G. K.; Ortiz, A.; Rassnick, S.; Russell, J. W.; Antal-Zimanyi, I. Synthesis and evaluation of 5,5-diphenylimidazolones as potent human neuropeptide Y5 receptor antagonists. Bioorg. Med. Chem. 2006, 14, 5517-5526.
119. Blum, C. A.; Zheng, X.; De Lombaert, S. Design, synthesis, and biological evaluation of substituted 2-cyclohexyl-4-phenyl-1H-imidazoles: potent and selective neuropeptide Y Y5-receptor antagonists. J. Med. Chem. 2004, 47, 2318-2325.
120. Guba, W.; Neidhart, W.; Nettekoven, M. Novel and potent NPY5 receptor antagonists derived from virtual screening and iterative parallel chemistry design. Bioorg. Med. Chem. Lett. 2005, 15, 1599-1603.
121. Nettekoven, M.; Guba, W.; Neidhart, W.; Mattei, P.; Pflieger, P.; Roche, O.; Taylor, S. Isomeric thiazole derivatives as ligands for the neuropeptide Y5 receptor. Bioorg. Med. Chem. Lett. 2005, 15, 3446-3449.
122. Nettekoven, M.; Guba, W.; Neidhart, W.; Mattei, P.; Pflieger, P.; Plancher, J. M.; Taylor, S. Aminothiazole derivatives as neuropeptide Y5 receptor ligands: finding the balance between affinity and physicochemical properties. Chem. Med. Chem. 2006, 1, 45-48.
123. Ishihara, A.; Kanatani, A.; Mashiko, S.; Tanaka, T.; Hidaka; M.; Gomori, A.; Iwaasa, H.; Murai, N,; Egashira, S.; Murai, T.; Mitobe, Y.; Matsushita, H.; Okamoto, O.; Sato, N.; Jitsuoka, M.; Fukuroda, T.; Ohe, T.; Guan, X.; MacNeil, D. J.; Van der Ploeg, L. H.; Nishikibe, M.; Ishii, Y.; Ihara, M.; Fukami, T. A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice. Proc. Natl. Acad. Sci. USA 2006, 103, 7154-7148.
124. Daniels, A. J.; Grizzle, M. K.; Wiard, R. P.; Matthews, J. E.; Heyer, D. Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist. Regul. Pept. 2002, 106, 47-54.
125. Della-Zuana, O.; Sadlo, M.; Germain, M.; Feletou, M.; Chamorro, S.; Tisserand, F.; de Montrion, C.; Boivin, J. F.; Duhault, J.; Boutin, J. A.; Levens, N. Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade. Int. J. Obes. Relat. Metab. Disord. 2001, 25, 84-94.
126. Mashiko, S.; Ishihata, A.; Iwaasa, H.; Sano, H.; Ito, J.; A.; Oda, Z.; Moriya, R.; Matsushita, H.; Jitsuoka, M.; Okamoto, O.; MacNeil, D. J.; van der Ploeg, L. H. T.; Fukami, T.; Kanatani, A. A pair-feeding study reveals that a Y5 antagonist causes weight loss in diet-induced obese mice by modulating food intake and energy expenditure. Mol. Pharmacol. 2007, 71, 602-608.
127. Iida, T.; Satoh, H.; Maeda, K.; Yamamoto, Y.; Asakawa, K.; Sawada, N.; Wada, T.; Kadowaki, C.; Itoh, T.; Mase, T.; Weissman, S. A.; Tschaen, D.; Krska, S.; Volante, R. P. Practical synthesis of a neuropeptide Y antagonist via stereoselective addition to a ketene. J. Org. Chem.
128. Dhillo, W. S.; Bloom, S. R. Gastrointestinal hormones and regulation of food intake. Horm. Metab. Res. 2004, 36, 846-851.