5-HT2C receptor modulators: A patent survey

Expert Opinion on Therapeutic Patents

Volumn 20, Issue 11, 2010, Pages 1429-1455

  Lee, Jinhwa ^a   Lee, Junwon ^a   Jung, Myung Eun ^a  

^a Green Cross Company   (South Korea)

Author keywords

5 HT; 5 HT2C receptor; 5 HT2C receptor agonist; 5 HT2C receptor antagonist; 5 HT2C receptor inverse agonist; 5 HT2C receptor modulator; anxiety; depression; drug addiction; erectile dysfunction; lorcaserin; obesity; Parkinson's disease; schizophrenia; urinary incontinence; vabicaserin

Indexed keywords

ATHX 105; AZAINDOLINE; AZEPINE DERIVATIVE; BENZAZEPINE DERIVATIVE; BENZYLMORPHOLINE; CHROMENE DERIVATIVE; INDOLE DERIVATIVE; LORCASERIN; LY 448100; MORPHOLINE DERIVATIVE; OXAZEPINE DERIVATIVE; PF 5208769; PIPERAZINE DERIVATIVE; PROXIMAGEN; PRX 00933; PYRIDOOXAZEPINE; PYRROLIDINE DERIVATIVE; SEROTONIN 2C AGONIST; SEROTONIN 2C RECEPTOR; TRYPTAMINE DERIVATIVE; UNCLASSIFIED DRUG; VABICASERIN; WAY 261240; WO 06103511; WO 08007664; WO 08117169; SEROTONIN 2 AGONIST; SEROTONIN 2 ANTAGONIST;

ALZHEIMER DISEASE; ANXIETY; BIPOLAR DEPRESSION; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DISEASE; CLINICAL TRIAL; DEPRESSION; DRUG BIOAVAILABILITY; DRUG DEPENDENCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; EPILEPSY; ERECTILE DYSFUNCTION; HUMAN; NONHUMAN; OBESITY; PARKINSON DISEASE; PROTEIN EXPRESSION; REVIEW; SCHIZOPHRENIA; URINE INCONTINENCE; ANIMAL; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG EFFECT; DRUG INDUSTRY; INVERSE AGONISM; METABOLISM; PATENT; PATHOPHYSIOLOGY;

ANIMALS; CENTRAL NERVOUS SYSTEM DISEASES; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUG INDUSTRY; DRUG INVERSE AGONISM; HUMANS; PATENTS AS TOPIC; RECEPTOR, SEROTONIN, 5-HT2C; SEROTONIN 5-HT2 RECEPTOR AGONISTS; SEROTONIN 5-HT2 RECEPTOR ANTAGONISTS;

EID: 77958485940     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543776.2010.518956     Document Type: Review

References (175)

1. Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999;38:1083-152
2. Rapport MM, Green AA, Page IH. Serum vasoconstrictor serotonin isolation and characterization. J Biol Chem 1948;176:1243-51
3. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biol Psychiatry 2006;59:1046-51
4. Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res 2008;195:198-213
5. Nisson BM. 5-Hydroxytryptamine 2C (5-HT2C) receptor agonists as potential antiobesity agents. J Med Chem 2006;49:4023-34
6. Shimada I, Maeno K, Kazuta K, et al. Synthesis and structure-activity relationships of a series of substituted 2-(1//-furo[2,3-g]indazol-1-yl) ethylamine derivatives as 5-HT2C receptor agonists. Biooorg Med Chem 2008;16:1966-82
7. Kelly AB, Clarke WP, Cunningham KA, et al. Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology 2008;55:969-76
8. Berg KA, Harvey JA, Spamprinato U, et al. Physiological and therapeutic relevance of constitutive activity of 5-HT2A and 5-HT2C receptors for the treatment of depression. Prog Brain Res 2008;172:287-305
9. Isaac M. Serotonergic 5-HT2C receptors as a potential therapeutic target for the design antiepileptic drugs. Curr Top Med Chem 2005;5:59-67
10. Pazos A, Hoyer D, Palacios JM. The binding of serotonergic ligands to the porcine choroid plexus characterization of a new type of serotonin recognition site. Eur J Pharmacol 1984;106:539-46
11. Burns CM, Chu H, Rueter SM, et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 1997;387:303-8
12. Fitzgerald LW, Iyer G, Conklin DS, et al. Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 1999;21:82S-90S
13. Herrick-Davis K, Grinde E, Niswender CM. Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. J Neurochem 1999;73:1711-17
14. Lopez-Gimenez JF, Mengod G, Palacios JM, et al. Regional distribution and cellular localization of 5-HT2C receptor mRNA in monkey brain: comparison with [3H]mesulergine binding sites and choline acetyltransferase mRNA. Synapse 2001;42:12-26
15. Fink KB, Gothert M. 5-HT receptor regulation of neurotransmitter release. Pharmacol Rev 2007;59:360-417
16. Jerman JC, Brough SJ, Gager T, et al. Pharmacological characterisation of human 5-HT2 receptor subtypes. Eur J Pharmacol 2001;414:23-30
17. Dutton AC, Barnes NM. Anti-obesity pharmacotherapy: future perspectives utilising 5-HT2C receptor agonists. Drug Discov Today Ther Strateg 2006;3:577-83
18. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United State, 2000s. JAMA 2004;291:1238-45
19. Miller KJ. Serotonin 5-HT2C receptor agonists: potential for the treatment ofobesity. Mol Interv 2005;5:282-91
20. Guy-Grand B, Apfelbaum M, Crepaldi G, et al. International trial of long-term dexfenfluramine in obesity. Lancet 1989;2:1142-5
21. Salmela PI, Sotaniemi EA, Viikari J, et al. Fenfluramine therapy in non-insulin-dependent diabetic patients: effects on body weight glucose homeostasis serum lipoproteins and antipyrine metabolism. Diabetes Care 1981;4:535-40
22. O'Connor HT, Richman RM, Steinbeck KS, et al. Dexfenfluramine treatment of obesity: a double blind trial with post trial follow up. Int J Obes Relat Metab Disord 1995;19:181-9
23. Garfield AS, Heisler LK. Pharmacological targeting of the serotonergic system for the treatment of obesity. J Physiol 2009;587:49-60
24. Nonogaki K, Strack AM, Dallman MF, et al. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 1998;4:1152-6
25. Tecott LH, Sun LM, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995;374:542-6
26. Wood MD, Reavill C, Trail B, et al. SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 2001;41:186-99
27. Griebel G, Perrault G, Sanger DJ. A comparative study of the effects of selective and non-selective 5-HT2 receptor subtype antagonists in rat and mouse models of anxiety. Neuropharmacology 1997;36:793-802
28. Kennett GA, Bailey F, Piper DC, et al. Effect of SB 200646A, a 5-HT2C/5-HT2B receptor antagonist in two conflict models of anxiety. Psychopharmacology 1995;118:178-82
29. Kennett GA, Wood MD, Bright F, et al. SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology 1997;36:609-20
30. de Mello Cruz AP, Pinheiro G, Alves SH, et al. Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze. Psychopharmacology 2005;182:345-54
31. Kahn RS, Wetzler S. m-Chlorophenylpiperazine as a probe of serotonin function. Biol Psychiatry 1991;30:1139-66
32. Campbell BM, Merchant KM. Serotonin 2C receptors within the basolateral amygdale induce acute fear-like responses in an open-field environment. Brain Res 2003;993:1-9
33. Bagdy G, Graf M, Anheuer ZE, et al. Anxiety-like effects induced by acute fluoxetine sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635. Int J Neuropsychopharmacol 2001;4:399-408
34. Roth BL, Shapiro DA. Insights into the structure and function of 5-HT2 family serotonin receptors reveal novel strategies for therapeutic target development. Exp Opin Ther Targets 2001;5:685-95
35. Iwamoto K, Nakatani N, Bundo M, et al. Altered RNA editing of serotonin 2C receptor in a rat model of depression. Neurosci Res 2005;53:69-76
36. Yang W, Wang Q, Kanes SJ, et al. Altered RNA editing of serotonin 5-HT2C receptor induced by interferon implication for depression associated with cytokine therapy. Brain Res Mol Brain Res 2004;124:70-8
37. Davidson JR, Meltzer-Brody SE. The underrecognition and undertreatment of depression: what is the breadth and depth of the problem? J Clin Psychiatry 1999;60:4-9
38. Kiloh LG, Andrews G, Neilson M. The long-term outcome of depressive illness. Br J Psychiatry 1988;153:752-7
39. Tran PV, Bymaster FP, McNamara RK, et al. Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol 2003;23:78-86
40. Bakish D, Lapierre YD, Weinstein R, et al. Ritanserin imipramine, and placebo in the treatment of dysthymic disorder. J Clin Psychopharmacol 1993;13:409-14
41. Eser D, Baghai TC, Moller HJ. Agomelatine: the evidence for its place in the treatment of depression. Core Evidence 2009;3:109-16
42. Nutt DJ, Forshall S, Bell C, et al. Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disoders. Eur Neuropsychopharmacol 1999;9:S81-6
43. 2A and 5-HT2C receptors. Trends Pharmacol Sci 2005;26:625-30
44. Cremers TI, Rea K, Bosker FJ, et al. Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 2007;32:1550-7
45. Cremers TI, Giorgetti M, Bosker FJ, et al. Inactivation of 5-HT2C receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 2004;29:1782-9
46. Millan MJ, Dekeyne A, Gobert A. Serotonin (5-HT) 2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 1998;37:953-5
47. Adell A, Castro E, Celada E, et al. Strategies for producing faster acting antidepressants. Drug Discov Today 2005;10(8):578-85
48. Sodhi MS, Burnet PW, MakoffAJ, et al. RNA editing of the 5-HT2C receptor is reduced in schizophrenia. Mol Psychiatry 2001;6:373-9
49. Wood M. Role of the 5-HT2C receptor in atypical antipsychotic: hero or villain? Curr Med Chem Cent Nerv Syst Agents 2005;5:63-6
50. Gobert A, Millan MJ. Serotonin (5-HT) 2A receptor activation enhances dialysate levels of dopamine and noradrenaline but not 5-HT in the frontal cortex of freely-moving rats. Neuropharmacology 1999;38:315-7
51. Gommans J, Hijzen TH, Pattij T, et al. Discriminative stimulus properties of røCPP and alprazolam are not mediated by anxiety. Pharmacol Biochem Behav 1999;64:385-7
52. Walker EA, Kohut SJ, Hass RW, et al. Selective and nonselective serotonin antagonists block the aversive stimulus properties ofMK-212 and rø-chlorophenylpiperazine (røCPP) in mice. Neuropharmacology 2005;49:1210-19
53. Burmeister JJ, Lungren EM, Kirschner KF, et al. Differential roles of 5-HT receptor subtypes in cue and cocaine reinstatement of cocaine-seeking behavior in rats. Neuropsychopharmacology 2004;29:660-8
54. Brodie MS, Bunney EB. Serotonin potentiates dopamine inhibition of ventral tegmental area neurons in vitro. J Neurophysiol 1996;76:2077-82
55. Cosford NDP, McDonald IA, Schweiger EJ. Chapter 7. Recent progress in antiepileptic drug research. Annu Rep Med Chem 1998;33:61-70
56. Heisler LK, Chu HM, Tecott LH. Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann NYAcad Sci 1998;861:74-8
57. Martin JR, Bos M, Jenck F, et al. 5-HT2C receptor qgonists: pharmacological characteristics and therapeutic potential. J Pharmacol Exp Ther 1998;286:913-24
58. Arjona AA, Pooler AM, Lee RK, et al. Effect of a 5-HT2C serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs. Brain Res 2002;951:135-40
59. Fox SH, Brotchie JM. 5-HT2C receptor antagonists enhance the behavioral response to dopamine D1 receptor agonists in the 6-hydroxydopamine-lesioned rat. Eur J Pharmacol 2000;398:59-64
60. Steers WD, Lee KS. Depression and incontinence. World J Urol 2001;19:351-7
61. Brennan PE, Whitlock GA, Ho DKH, et al. Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence. Bioorg Med Chem Lett 2009;19:4999-5003
62. Hemmie HGB. Hot flushes and serotonin. Menopause Int 2002;8:30-4
63. Waldinger MD, Berendsen HHG, Schwitzer DH. Treatment of hot flushes with mirtazapine: four case report. Maturitas 2000;36:165-8
64. Michae JB, Bjorn MN. New 5-HT2C receptor agonist. Expert Opin Ther Patents 2003;13:1691-705
65. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance ofmale rats. Life Sci 1989;45:1263-70
66. Arena Pharmaceuticals, Inc. 5-HT2C receptor modulators. WO03086306; 2003
67. Smith BM, Smith JM, Tsai JH, et al. Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1 H-3-benzazepine (locarserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity. J Med Chem 2008;51:305-13
68. 70th Scientific Sessions. Lorcaserin, a selecetive 5-HT2C agonist, is efficacious for weight loss across patient subgroups. American Diabetes Association, Orlando, FL;2010
69. 70th Scientific Sessions. Changes in glucose tolerance and cardiovascular risk factors after 52 weeks of treatment with lorcaserin. American Diabetes Association, Orlando, FL; 2010
70. Arena Pharmaceuticals, Inc. Benzazephine derivatives useful for the treatment of 5-HT2C receptor assodiated diseases. WO05003096; 2005
71. Arena Pharmaceutical, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5-HT2C receptor associated diseases. WO05042490; 2005
72. Arena Pharmaceuticals, Inc. Benzazepine derivatives and methods of prophylaxis or treatment of 5-HT2C receptor associated diseases. WO05042491; 2005
73. Smith BM, Smith JM, Tsai JH, et al. Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity. Bioorg Med Chem Lett 2005;15:1467-70
74. Ciba-Geigy Corp. Anorexigenic tetrahydrobenzazepines. US3716639; 1973
75. Millan MJ, Newman-Tancredi A, Quentric Y, et al. The " selective" dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors. Psychopharmacology 2001;156:58-62
76. Porter RHP, Benwell KR, Lamb H, et al. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 1999;128:13-20
77. Arena Pharmaceuticals, Inc. N-Phenyl-piperazine derivatives and methods of prophylaxis or treatment of 5HT2C receptor associated diseases. WO05016902; 2005
78. Arena Pharmaceuticals, Inc. N-Biaryl and N-arylheteroaryl piperazine derivatives as modulator of the 5HT2C receptor useful for the treatment of disorders related thereto. WO06065600; 2006
79. Arena Pharmaceuticals, Inc. N-Biaryl and N-arylheteroaryl 2-substituted piperazine derivatives as modulator of the 5HT2C receptor useful for the treatment of disorders related thereto. WO06065706; 2006
80. Wyeth [Pfizer, Inc.]. [1,4]Diazepino [6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents. WO03091250; 2003
81. Neuroscience 2006: 36th Annual Meeting. In vitro pharmacological profile of SCA-136, a novel 5-HT2C receptor selective agonist. Society for Neuroscience, Atlanta, GA; 2006
82. 231st ACS National Meeting. Discovery of SCA-136, a novel 5-HT2C agonist, for the treatment of Schizophrenia. American Chemical Society, Atlanta, GA; 2006
83. Wyeth [Pfizer, Inc.]. 1,2,3,4,7,8Hexahydro-6H-[1,4]Diazepino [6,7,1-ij]quinoline derivatives as antipsychotic and antiobesity agents. WO03091251; 2003
84. Wyeth [Pfizer, Inc.]. Cyclopenta[b][1,4] diazepino[6,7,1-hi]indoles and derivatives. WO02042304; 2002
85. Dunlop J, Sabb AL, Mazandarani H, et al. WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi] indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity. J Pharmacol Exp Ther 2005;313:862-9
86. Sabb AL, Vogel RL, Welmaker GS, et al. Cycloalkyl[b][1,4] benzodiazepinoindoles are agonists at the human 5-HT2C receptor. Bioorg Med Chem Lett 2004;14:2603-7
87. Wyeth [Pfizer, Inc.]. Chromane and chromene derivatives and uses thereof. WO06116165; 2006
88. 238th ACS National Meeting. (8-Phenylchroman-2-yl)methanamine analogs as potent 5-HT2C receptor agonists. American Chemical Society, Washington, DC; 2009
89. Wyeth [Pfizer, Inc.]. Dihydrobenzofuranyl alkanamines and pharmaceutical compositions containing them. WO05040146; 2005
90. Wyeth [Pfizer, Inc.]. Dihydrobenzofuranyl alkanamine derivatives as 5HT2C agonists. WO05044812; 2005
91. Wyeth [Pfizer, Inc.]. Dihydrobenzofuran derivatives and uses thereof. WO06116150; 2006
92. Wyeth [Pfizer, Inc.]. Benzodioxane and benzodioxolane derivatives and uses thereof WO06116158; 2006
93. Wyeth [Pfizer, Inc.]. Benzodioxane derivatives and uses thereof. WO08052096; 2008
94. Wyeth [Pfizer, Inc.]. Benzoxazine derivatives and uses thereof. WO08052075; 2008
95. Wyeth [Pfizer, Inc.]. Benzoxathine and benzoxathiole derivatives and uses thereof WO08052078; 2008
96. Wyeth [Pfizer, Inc.]. Substituted indolizines and derivatives as CNS agents. WO6050007; 2006
97. Pfizer Products, Inc. 5-HT2C receptor modulators. WO06103511; 2006
98. Andrews MD, Green MP, Allerton CMN, et al. Design and synthesis of piperazinylpyrimidinones as novel selective 5-HT2C agonists. Bioorg Med Chem Lett 2009;19:5346-50
99. Allerton CMN, Andrews MD, Blagg J, et al. Design and synthesis of pyridazinone-based 5-HT2C agonists. Bioorg Med Chem Lett 2009;19:5791-5
100. Pfizer, Inc. Pyrimido[4,5-¿/]azepine derivatives as 5-HT2C agonists. WO08117169; 2008
101. Takeda Pharmaceutical Co. Ltd. Fused heterocyclic compound and use thereof. WO07132841; 2007
102. Takeda Pharmaceutical Co. Ltd. Benzoxazepine derivatives and use thereof. WO08108445; 2008
103. Takeda Pharmaceutical Co. Ltd. Tricyclic heterocyclic compound and use thereof. WO08007661; 2008
104. Takeda Pharmaceutical Co. Ltd. Pyridooxazepine derivative and use thereof. WO09063991; 2009
105. Takeda Pharmaceutical Co. Ltd. Condensed pyridine derivative and use thereof. WO09063992; 2009
106. Takeda Pharmaceutical Co. Ltd. Fused pyridine derivative and use thereof. WO09063993; 2009
107. Takeda Pharmaceutical Co. Ltd. Bicyclic heterocyclic compound and use thereof. WO08007664; 2008
108. Eli Lilly and Co. Benzofurylpiperazines and benzofurylhomopiperazines: Serotonin agonists. EP1204654; 2003
109. Sarabu R. Metabolic diseases drug discovery world summit. Expert Opin Invest Drugs 2003;12:1721-6
110. Eli Lilly and Co. 6-Substituted 2,3,4,5-tetrahydro-1//-benzo[¿/] azepines as 5-HT2C receptor agonists. WO05082859; 2005
111. 3rd Anglo-Swedish Medicinal Chemistry Symposium. The discovery and development of selective 5-HT2C receptor agonists. Are, Sweden: Swedish Academy of Pharmaceutical Sciences; 2007
112. Eli Lilly and Co. 6-(2,2,2-Trifluoroethylamino)-7-chloro-2,3,4,5- tetrahydro-1//-benzo[¿/]azepine as a 5-HT2C receptor agoinst. WO05019180; 2005
113. Eli Lilly and Co. 6-Substituted-2,3,4,5-tetrahydro-1//-benzo[¿/] azepines as 5-HT2C receptor agonists. WO07028082; 2007
114. Eli Lilly and Co. 6-Arylalkylamino-2,3,4,5-tetrahydro-1//-benzo[¿/ ]azepines as 5-HT2C receptor agonists. WO07028083; 2007
115. Eli Lilly and Co. 6-Substituted 23,4,5-tetrahydro-1//-benzo[¿/] azepines as 5-HT2C receptor agonists. WO07028131; 2007
116. Eli Lilly and Co. 6-./V-Linked heterocycle-substituted 23,4,5-tetrahydro-1//-benzo[¿/]azepines as 5-HT2C receptor agonists. WO07028132; 2007
117. F. Hoffmann-La Roche AG; Vernalis Research Ltd. Piperazine derivatives. WO0201169; 2002
118. Rover S, Adams DR, Benardeau A, et al. Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a] indoles as 5-HT2C receptor agonists. Bioorg Med Chem Lett 2005;15:3604-8
119. F. Hoffmann-La Roche AG; Vernalis Research Ltd. 5HT2C receptor agonists for the treatment of diabetes and obesity. WO05000849; 2005
120. Richter HGF, Adams DR, Benardeau A, et al. Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5] pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2C receptor agonists. Bioorg Med Chem Lett 2006;16:1207-11
121. F. Hoffmann-La Roche AG; Vernalis Research Ltd. Morpholines as 5HT2C agonists. WO06077025; 2006
122. F. Hoffmann-La Roche AG; Vernalis Research Ltd. Indoline derivatives and their use as 5-HT2C receptor ligands. US02044152; 2002
123. Vernalis Research Ltd. Indole derivatives process for their preparation, pharmaceutical compositions containing them and their medicinal application. US6706750; 2004
124. Vernalis Research Ltd. Condensed indoline derivativesand their use as 5HT, in particular 5H2C, receptor ligands. US6962939; 2005
125. Bentley JM, Adams DR, Bebbington D, et al. Indoline derivatives as 5-HT2C receptor agonists. Bioorg Med Chem Lett 2006;16:1207-11
126. F. Hoffmann-La Roche AG; Vernalis Research Ltd. New aza-indolyl derivatives. WO01066548; 2001
127. F. Hoffmann-La Roche AG; Vernalis Research Ltd. Indole derivatives and their use as 5-HT2B and 5-HT2C receptor lignads. WO02051844; 2002
128. Athersys reports 2008 third quarter results. Athersys, Inc. Cleveland, OH: Press Release, 2008. Available from: files.shareholder. com/downloads/ ATHERSYS/969028859x0x248447/38799266-246f-40cd-b75f-65d317a65397/ ATHX-News-2008-11-10-General-Releases.pdf [Last accessed 22 July 2010]
129. Athersys reports 2008 forth quarter and 2008 annual results. Athersys, Inc. Cleveland, OH: Press Release, 2009. Available from: files.shareholder. com/downloads/ATHERSYS/969127794x0x279688/6e7a970e-79f7-4178-a8f5-196b41891d80/ ATHX-News-2009-3-12-General-Releases.pdf [Last accessed 22 July 2010]
130. Treatment for obesity. Athersys, Inc. Cleveland, OH: Product Candidates, 2010. Available from: www.athersys.com/Home/ProductCandidates/ TreatmentsforObesity/tabid/70/Default.aspx
131. 2nd Annual Drug Development for Obesity and Diabetes. Promising mechanisms of action and targets case studies: GLP-1 analogues, SIRT1 activators, GPCRs, PPAR gamma agonists and 5-HT2C. Marcus Events, London; 2008
132. Athersys announces summary results for phase I safety study of its novel obesity drug. Athersys, Inc. Cleveland, OH: Press Release, 2008. Available from: http://files.shareholder.com/downloads/ATHERSYS/969127794x0x174910/055a2c62- 2f04-4ac9-8f92-c07d440fcbb6/ATHX-News- 2008-2-27-General-Releases.pdf [Last accessed 22 July 2010]
133. Athersys, Inc. Substituted azepine derivatives as serotonin receptor modulators. WO06004931; 2006
134. Athersys, Inc. Thiophenyl and pyrrolyl azepines as serotonin 5-HT2C receptor ligands and uses thereof. WO07084622; 2007
135. Athersys, Inc. Tricyclic heteroaryl piperazines, pyrrolidines and azetidines as serotonin receptor modulator. WO06028961; 2006
136. Athersys, Inc. Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators. WO07081299; 2007
137. Huck BR, Llamas L, Robarge MJ, et al. The design and synthesis of tricyclic single-nitron scaffold that serves as a 5-HT2C receptor agonist. Bioorg Med Chem Lett 2006;16:4130-4
138. Huck BR, Llamas L, Rovbarge MJ, et al. The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT2C receptor agonists. Bioorg Med Chem Lett 2006;16:2891-4
139. Svartengren J, Fholenhag K, Modiri AR, et al. Preclinical in vivo pharmacology of BVT.933, a selective 5-HT2C receptor agonist. Soc Neurosci Abstr 2003;29:509.9
140. Biovitrum completes successful phase Iia trial for anti-obesity treatment. Swedish Orphan Biovitrum AB. Stockholm: Press Release 2002. Available from: www.biovitrum.com/templates/PressRelease-Hugin.aspx?id=598&Release= http://cws.huginonline.com/S/134557/PR/200202/1139285.xml [Last accessed 22 July 2010]
141. Biovitrum AB. Novel compounds, their use and preparation. WO04000830; 2003
142. Forest Laboratories Holdings Ltd. Pyridoazepine derivatives. WO07140213; 2007
143. NPS Allelix Corp. Tetrahydro-5//-pyrido [2,3-?]azepines as 5-HT2C ligands. WO08009125; 2008
144. Cascade Therapeutics, Inc. Compound with activity at the 5-HT2C receptor. WO09079765; 2009
145. Bayer Pharmaceuticals Co. Tetrahydro-5-r/-pyrimido[4,5-¿/]azepine derivatives useful for the treatment of diseases associated with the 5-HT2C receptor. WO06044762; 2006
146. Bayer Co. Benzothieno[3,2-¿̀]pyrazolyl and benzofurano[3,2-¿̀]pyrazolyl compounds, their use in diseases associated with the 5-HT2C receptor and intermediate compounds thereof WO03057161; 2003
147. Bayer Co. Cyclohexano-and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-HT2C receptor. WO03057213; 2003
148. Bayer Co. 1//-Pyrazolyl derivative compounds, for the use in diseases associated with the 5-HT2C recepteor. WO03057673; 2003
149. Bayer Co. 4-Sulfide/sulfoxide/sulfonyl-1//-pyrazolyl derivative compounds, for the use in diseases associated with the 5-HT2C recepteor. WO03057674; 2003
150. Wacker DA, Varnes JG, Malmstrom SE, et al. Discovery of (7ü)-9-ethyl-1,3,4, 10b-tetrahydro-7-trifluoromethylpyrazino [2,1-?]insodindol-6(2//)-one, a selective, orally active agonist of the 5-HT2C receptor. J Med Chem 2007;50:1365-79
151. Bristol-Myer Squibb Co. Modulators of serotonin receptor. US7244843; 2007
152. Kimura Y, Hatanake K, Naitou Y, et al. Pharmacological profile ofYM348, a novel, potent and orally active 5-HT2C receptor agonist. Eur J Pharmacol 2004;483:37-43
153. Hayashi A, Sonoda R, Kimura Y, et al. Antiobesity effect ofYM348, a novel 5-HT2C receptor agonist, in Zucker rats. Brain Res 2004;1011:221-7
154. Yamanouchi Pharmaceutical Co. Ltd. Froindazole derivative. WO01083487; 2001
155. Yamanouchi Pharmaceutical Co. Ltd. Benzazepine derivatives. WO02074746; 2002
156. Shimada I, Maeno K, Kondoh Y, et al. Synthesis and structure-activity relationships of a series of benzazepine derivatives as 5-HT2C receptor agonists. Bioorg Med Chem 2008;16:3309-20
157. Cho SJ, Jensen NH, Kurome T, et al. Selective 5-HT2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action. J Med Chem 2009;52:1885-902
158. Les Laboratories Servier. Indoline compounds, a process for their preparation and pharmaceutical compositions containing them. US6759421; 2004
159. Neuroscience 2007: 37th Annual Meeting. S32006, a novel inverse agonist at 5-HT2C receptor: and in vitro and in vivo characterization. Society for Neuroscience, San Diego, CA; 2007
160. SmithKline Beecham plc. Indoine derivatives useful as 5-HT-2C receptor antagonist. WO97048699; 1997
161. Bromidge SM, Dabbs S, Davies DT, et al. Biarylcarbamoylindolines are novel and selective 5-HT2C receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl] carbamoyl]-6- trifluoromerhylindoline (SB-243213) as a potent antidepressant/anxiolytic agent. J Med Chem 2000;43:1123-34
162. SmithKline Beecham plc. Indoline derivatives useful as 5-HT-2C receptor antagonists. WO97048700; 1997
163. Bronide SM, Davies S, Duckworth M, et al. 1-[2-[(Heteroarylmethoxy)aryl] carbamoyl]indulines are selective and orally active 5-HT2C receptor inverse agonists. Bioorg Med Chem Lett 2000;10:1867-70
164. SmithKline Beecham plc. Indoline derivatives as 5HT2C antagonists. WO02014273; 2002
165. Glaxo Group Ltd. Cyclic urea derivatives with 5-HT2C receptor activity. WO03057220; 2003
166. Goodacre CJ, Bromidge SM, Clapham D, et al. A series of bisaryl imidazolidn-2-one has shown to be selective and orally active 5-HT2C receptor antagonists. Bioorg Med Chem Lett 2005;15:4989-93
167. Glaxo Group Ltd. Compounds having affinity at 5HT2C receptor and use thereof in therapy. WO03089409; 2003
168. Micheli F, Pasquarello A, Tedesco G, et al. Diaryl substituted pyrrolidinones pyrrolones as 5-HT2C inhibitors: Synthesis and biological evaluation. Bioorg Med Chem Lett 2006;16:3906-12
169. Glaxo Group Ltd. Compounds having activity at 5HT2C receptor and uses thereof EP1599445; 2004
170. Glaxo Group Ltd. Compounds having activity at 5HT2C receptor and uses thereof WO04081010; 2004
171. Hammprecht D, Micheli F, Tedesco G, et al. 5-HT2C antagonists based on fused heterotricyclic templates: Design, synthesis and biological evaluation. Bioorg Med Chem Lett 2007;17:424-7
172. Glaxo Group Ltd. Compounds having activity at 5HT2C receptor and uses thereof WO04089897; 2004
173. Hammprecht D, Micheli F, Tedesco G, et al. Isoindolone derivatives, a new class of 5-HT2C antagonists: synthesis and biological evaluation. Bioorg Med Chem Lett 2007;17:428-33
174. Korea Research Institute ofChemical Technology. Novel indol carboxylic acid bipyidyl carboxamide derivatives, pharmaceutically acceptable salt thereof, preparation method and composition containing the same as an active ingredient. WO09125923; 2009
175. Park CM, Kim SY, Park WK, et al. Synthesis and structure-activity relationship of 1H-indole-3-carboxylic acid pyridine-3-ylamides: a novel series of 5-HT2C receptor antagonists. Bioorg Med Chem Lett 2008;18:3844-7