(3-Phenylsulfonylcycloalkano[e and d]pyrazolo[1,5- a]pyrimidin-2-yl)amines: Potent and selective antagonists of the serotonin 5-HT6 receptor

Journal of Medicinal Chemistry

Volumn 53, Issue 14, 2010, Pages 5186-5196

  Ivachtchenko, Alexandre V ^a,b   Dmitriev, Dmitri E ^a   Golovina, Elena S ^a   Kadieva, Madina G ^a   Koryakova, Angela G ^a   Kysil, Volodymyr M ^b   Mitkin, Oleg D ^a   Okun, Ilya M ^b   Tkachenko, Sergey E ^b   Vorobiev, Anton A ^a  

^a Chemical Diversity Research Institute   (Russian Federation)

^b CHEMDIV INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

N METHYL (3 PHENYLSULFONYL) 7,8 DIHYDRO 6H CYCLOPENTA[E]PYRAZOLO[1,5 A]PYRIMIDIN 2 AMINE; POTASSIUM CHANNEL HERG; PYRAZOLO[1,5 A]PYRIMIDINE DERIVATIVE; SEROTONIN 2B RECEPTOR; SEROTONIN 6 ANTAGONIST; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG ACTIVITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG SYNTHESIS; HUMAN; HUMAN CELL;

AMINES; CELL LINE; CRYSTALLOGRAPHY, X-RAY; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRAZOLES; PYRIMIDINES; RADIOLIGAND ASSAY; RECEPTOR, SEROTONIN, 5-HT2B; RECEPTORS, SEROTONIN; SEROTONIN ANTAGONISTS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 77954744296     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100350r     Document Type: Article

References (40)

1. Monsma, F. J., Jr.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley, D. R. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs Mol. Pharmacol. 1993, 43, 320-327
2. Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Lachowicz, J. E.; Meltzer, H. Y.; Sibley, D. R.; Roth, B. L.; Hamblin, M. W. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor J. Neurochem. 1996, 66, 47-56
3. Wesolowska, A. The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors Eur. J. Pharmacol. 2008, 580, 355-360
4. Wesolowska, A.; Nikiforuk, A. Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression Neuropharmacology 2007, 52, 1274-1283
5. Hirst, W. D.; Stean, T. O.; Rogers, D. C.; Sunter, D.; Pugh, P.; Moss, S. F.; Bromidge, S. M.; Riley, G.; Smith, D. R.; Bartlett, S.; Heidbreder, C. A.; Atkins, A. R.; Lacroix, L. P.; Dawson, L. A.; Foley, A. G.; Regan, C. M.; Upton, N. SB-399885 is a potent, selective 5-HT6 receptor antagonist with cognitive enhancing properties in aged rat water maze and novel object recognition models Eur. J. Pharmacol. 2006, 553, 109-19
6. Perez-García, G.; Meneses, A. Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task Pharmacol., Biochem. Behav. 2005, 81, 673-682
7. Wesolowska, A.; Nikiforuk, A. The selective 5-HT(6) receptor antagonist SB-399885 enhances anti-immobility action of antidepressants in rats Eur. J. Pharmacol. 2008, 582, 88-93
8. Dawson, L. A.; Nguyen, H. Q.; Li, P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus Neuropsychopharmacology 2001, 25, 662-668
9. Foley, A. G.; Murphy, K. J.; Hirst, W. D.; Gallagher, H. C.; Hagan, J. J.; Upton, N.; Walsh, S.; Regan, C.,M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats Neuropsychopharmacology 2004, 29, 93-100
10. 6 receptor antagonist J. Med. Chem. 2003, 46, 1273-1276
11. King, M. V.; Woolley, M. L.; Topham, I. A.; Sleight, A. J.; Marsden, C. A.; Fone, K. C. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation - an effect sensitive to NMDA receptor antagonism Neuropharmacology 2004, 47, 195-204
12. 6 receptor ligands as potential cognitive enhancers and antiobesity agents Drug Discovery Today 2006, 11, 283-299
13. Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.; Monsma, F. J., Jr.; Shen, Y.; Meltzer, H. Y.; Sibley, D. R. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410
14. Heal, D. J.; Smith, S. L.; Fisas, A.; Codony, X.; Buschmann, H. Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders Pharmacol. Ther. 2008, 117, 207-231
15. 6 receptor Drugs Future 2005, 30, 479-495
16. Woolley, M. L. 5-HT6 receptors Curr. Drug Targets: CNS Neurol. Disord. 2004, 3, 59-79
17. Vicker, S. P.; Dourish, C. T. Serotonin receptor ligands and the treatment of obesity Curr. Opin. Invest. Drugs. 2004, 5, 377-388
18. http://www.biospace.com/news-story.aspx?NewsEntityId=141148.
19. Tkachenko, S.; Ivachtchenko, A.; Khvat, A.; Okun, I.; Lavrovsky, Y.; Salimov, R. Discovery and Preclinical Studies of AVN-322 Highly Selective and Potent 5-HT6 Antagonist for Cognition Enhancement in Treating Neurodegenerative Diseases. Abstracts of Papers, 9th International Conference AD/PD 2009, Prague, Czech Republic, 2009; Karger: Basel, Switzerland, 2009; p 945.
20. Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.; Glennon, R. A. N 1-(Benzenesulfonyl) tryptamines as novel 5-HT6 antagonists Bioorg. Med. Chem. Lett. 2000, 10, 2295-2299
21. Kim, H.-J.; Doddareddy, M. R.; Choo, H.; Cho, Y. S.; No, K. T.; Park, W.-K.; Pae, A. N. J. Chem. Inf. Model. 2008, 48, 197-206
22. López-Rodríguez, M. L.; Benhamu, B.; de la Fuente, T.; Sanz, A.; Pardo, L.; Campillo, M. A three-dimensional pharmacophore model for 5-hydroxytryptamine6 (5-HT6) receptor antagonists J. Med. Chem. 2005, 48, 4216-4219
23. Bromidge, S. M. Potent and selective 5-HT6 receptor antagonists Spec. Publ. R. Soc. Chem. 2001, 264, 101-119
24. 6 receptors in rat, pig and human brain tissue Br. J. Pharmacol. 2000, 130, 1597-1605
25. 6 receptors Bioorg. Med. Chem. Lett., 2004, 14, 4569-4573
26. Dukat, M.; Mosier, P. D.; Kolanos, R.; Roth, B. L.; Glennon, R. A. Binding of serotonin and N 1-benzenesulfonyltryptamine-related analogs at human 5-HT6 serotonin receptors: receptor modeling studies J. Med. Chem. 2008, 51, 603-611
27. Singer, J. M.; Wilson, M. W.; Johnson, P. D.; Graham, S. R.; Cooke, L. W.; Roof, R. L.; Boxer, P. A.; Gold, L. H.; Meltzer, L. T.; Janssen, A.; Roush, N.; Campbell, J. E.; Su, T. Z.; Hurst, S. I.; Stoner, C. L.; Schwarz, J. B. Synthesis and SAR of tolylamine 5-HT6 antagonists Bioorg. Med. Chem. Lett. 2009, 19, 2409-2412
28. Ivachtchenko, A. V.; Mitkin, O. D.; Tkachenko, S. E.; Okun, Kysil, V. M. 8-Sulfonyl-substitutedtetrahydro-1 H -pyrido[4,3- b ]indolesas 5-HT receptor antagonists Eur. J. Med. Chem. 2010, 45, 782-789
29. Seong, C.,M.; Park, W. K.; Park, C. M.; Kong, J. Y.; Park, N. S. Discovery of 3-aryl-3-methyl-1 H -quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists Bioorg. Med. Chem. Lett. 2008, 18, 738-743
30. Upton, N; Chuang, T. T.; Hunter, A. J.; Virley, D. J. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease Neurotherapeutics 2008, 5, 458-469
31. Zhao, S.-H.; Berger, J.; Clark, R. D.; Sethofer, S. G.; Krauss, N. E.; Brothers, J. M.; Martin, R. S.; Misner, D. L.; Schwabd, D.; Alexandrova, L. 3,4-Dihydro-2 H -benzo[1,4]oxazine derivatives as 5-HT6 receptor antagonists Bioorg. Med. Chem. Lett. 2007, 17, 3504-3507
32. http://clinicaltrials.gov/ct2/show/NCT00348192.
33. 6 receptor antagonists Bioorg. Med. Chem. Lett. 2010, 20, 2133-2136
34. Bajwa, J. S.; Sykes, P. J. Synthesis and structure of same azolo[ a ]pyrimidines, 2,6,7,8-tetrahydro-1 H -cyclopenta[ e ]azolo[ a ]pyrimidines, 6,7-dihydro-5 H -ceclopenta[ f ]azolo[ a ]pyrimidines, 7,8-dihydro-6 H -cyclopenta[ f ]- s -triazolo[4,3- b ]pyrimidine, 5,6,7,8-tetrahydroazolo[ b ]quinozalines, 6,7,8,9-tetrahydroazolo[ a ]quinozalines, and 7,8,9,10-tetrahydro- s -triazolo[3,4-a]phthalazine J. Chem. Soc., Perkin Trans. 1 1979, 1, 3085-3094
35. Augustin, M.; Schmidt, R.; Rudors, W.-D. Synthese und reaktivitat von phenylsulfonyl-cyan-keten- S, S -acetalen Z. Chem. 1977, 17, 289-290
36. Pugmire, R. J.; Robins, M. J.; Grant, D. M.; Robins, R. K. Carbon-13 magnetic resonance. XX. 4-Azaindene (pyrrocoline) and related bridgehead nitrogen heterocycles J. Am. Chem. Soc. 1971, 93, 1887-1893
37. Vartanyan, M. A.; Eliseev, O. L.; Skov, Kh. R.; Karakhanov, R. A. Synthesis of acetonylmalonaldehyde and its interaction with aminoazoles Russ. Chem. Bull. 1997, 46, 1178-1179
38. Radioligand binding assays were performed by MDS Pharma Services (Taipei, Taiwan) in accordance with their internally developed assays, briefly described in the Supporting Information.
39. Rothman, R. B.; Baumann, M. H.; Savage, J. E.; Rauser, L.; McBride, A.; Hufeisen, S. J.; Roth, B. L. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications Circulation 2000, 102, 2836-2841
40. Yao, X.; Anderson, D. L.; Ross, S. A.; Lang, D. G.; Desai, B. Z.; Cooper, D. C.; Wheelan, P.; McIntyre, M. S.; Bergquist, M. L.; MacKenzie, K. I.; Becherer, J. D.; Hashim, M. A. Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model Br. J. Pharmacol. 2008, 154, 1446-1456