[3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1H-indoles: Synthesis, SAR and biological evaluation as a novel class of 5-HT6 Receptor Antagonists
In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT 6 receptor (5-HT 6 R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Meth...
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| Published in | Journal of chemical sciences (Bangalore, India) Vol. 127; no. 3; pp. 439 - 445 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | English |
| Published |
New Delhi
Springer India
01.03.2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0974-3626 0973-7103 |
| DOI | 10.1007/s12039-015-0800-7 |
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| Abstract | In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT
6
receptor (5-HT
6
R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1
H
-indole derivatives as potent and selective 5-HT
6
R antagonists. The lead compound from this series shows potent
in vitro
binding affinity, functional antagonistic activity at 5-HT
6
R, good pharmacokinetic profile, excellent selectivity and no Cytochrome P450 liabilities.
Graphical Abstract
We report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1
H
-indole derivatives as potent and selective 5-HT
6
R antagonists. The lead compound from this series shows potent
in vitro
binding affinity, functional antagonistic activity at 5-HT
6
R, good pharmacokinetic profile, excellent selectivity and no CYP liabilities. |
|---|---|
| AbstractList | In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT
6
receptor (5-HT
6
R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1
H
-indole derivatives as potent and selective 5-HT
6
R antagonists. The lead compound from this series shows potent
in vitro
binding affinity, functional antagonistic activity at 5-HT
6
R, good pharmacokinetic profile, excellent selectivity and no Cytochrome P450 liabilities.
Graphical Abstract
We report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1
H
-indole derivatives as potent and selective 5-HT
6
R antagonists. The lead compound from this series shows potent
in vitro
binding affinity, functional antagonistic activity at 5-HT
6
R, good pharmacokinetic profile, excellent selectivity and no CYP liabilities. |
| Author | BADANGE, RAJESH KUMAR KHAGGA, MUKKANTI KANDUKURI, KIRAN KUMAR NIROGI, RAMAKRISHNA V S |
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| Cites_doi | 10.1016/j.bmcl.2011.05.106 10.1021/jm050247c 10.1016/S0006-8993(96)01224-3 10.1016/j.ddstr.2004.08.003 10.2174/156720510791383831 10.3987/R-1984-01-0195 10.2174/156802610791111542 10.1038/sj.bjp.0706827 10.1002/gps.938 10.1016/S0960-894X(00)00453-4 10.1016/j.amjmed.2006.08.036 10.1016/S0893-133X(01)00265-2 10.32725/jab.2007.008 10.1017/S1461145710000659 |
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| Keywords | indoles pharmacokinetic profile R antagonists cross selectivity [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1 cognitive impairment structure activity relationship 5-HT |
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| References | Nirogi R, Dwarampudi A, Kambhampati R, Bhatta V, Kota L, Shinde A, Badange R, Jayarajan P, Bhyrapuneni G and Dubey P K 2011 Bioorg. Med. Chem. Lett. 21 4577 Johnson C N, Roland A and Upton N 2004 Drug Discov. Today: Therapeutic Strategies1 13 Glennon R A, Siripurapu U, Roth B L, Kolanos R, Bondarev M L, Sikazwe D, Lee M and Dukat M 2010 Curr. Top. Med. Chem.10 579 Farlow M R and Cummings J L 2007 Am. J. Med.120 388 Maher-Edwards G, Zvartau-Hind M, Hunter A J, Gold M, Hopton G, Jacobs G, Davy M and Williams P 2010 Curr. Alzheimer. Res.7 374 Arnt J, Bang-Andersen B, Grayson B, Bymaster F P, Cohen M P, DeLapp N W, Giethlen B, Kreilgaard M, McKinzie D L, Neill J C, Nelson D L, Nielsen S M, Poulsen M N, Schaus J M and Witten L M 2010 Int. J. Neuropsychopharmacol.13 1021 Dawson L A, Nguyen H Q and Li P 2001 Neuropsychopharmacology25 662 Gerard C, Martres M P, Lefevre K, Miquel M C, Verge D, Lanfumey L, Doucet E, Hamon M and Mestikawy S E 1997 Brain Res.746 207 Isensee K, Petroianu G and Stark H 2007 J. Appl. Biomed.5 57 Gonzalo R, Elisabeth S, Marta P, Pilar P, Xavier C, Jorg H, Helmut B and Petrus J P 2006 Br. J. Pharmacol.148 1133 Tsai Y, Dukat M, Slassi A, MacLean N, Demchyshyn L and Savage J E et al. 2000 Bioorg. Med. Chem. Lett.10 2295 Zhou P, Kelly MG and Li Y WO 2002051832 (a) Clark R D and Repke D B 1984 Heterocycles22 195; (b) Batcho A D and Leimgruber W 1985 Org. Synth.63 214 Lopez-Rodrıguez ML, Bellinda B, Tania de la F, Arantxa S, Leonardo P and Mercedes C 2005 J. Med. Chem.48 4216 Danysz W and Parsons C G 2003 Int. J. Geriatr. Psychiatry18 Suppl 1: S23 800_CR4 800_CR5 800_CR2 800_CR3 800_CR1 800_CR8 800_CR9 800_CR15 800_CR6 800_CR14 800_CR7 800_CR13 800_CR12 800_CR11 800_CR10 |
| References_xml | – reference: Gerard C, Martres M P, Lefevre K, Miquel M C, Verge D, Lanfumey L, Doucet E, Hamon M and Mestikawy S E 1997 Brain Res.746 207 – reference: Isensee K, Petroianu G and Stark H 2007 J. Appl. Biomed.5 57 – reference: Danysz W and Parsons C G 2003 Int. J. Geriatr. Psychiatry18 Suppl 1: S23 – reference: Lopez-Rodrıguez ML, Bellinda B, Tania de la F, Arantxa S, Leonardo P and Mercedes C 2005 J. Med. Chem.48 4216 – reference: Nirogi R, Dwarampudi A, Kambhampati R, Bhatta V, Kota L, Shinde A, Badange R, Jayarajan P, Bhyrapuneni G and Dubey P K 2011 Bioorg. Med. Chem. Lett. 21 4577 – reference: Dawson L A, Nguyen H Q and Li P 2001 Neuropsychopharmacology25 662 – reference: Johnson C N, Roland A and Upton N 2004 Drug Discov. Today: Therapeutic Strategies1 13 – reference: (a) Clark R D and Repke D B 1984 Heterocycles22 195; (b) Batcho A D and Leimgruber W 1985 Org. Synth.63 214 – reference: Gonzalo R, Elisabeth S, Marta P, Pilar P, Xavier C, Jorg H, Helmut B and Petrus J P 2006 Br. J. Pharmacol.148 1133 – reference: Zhou P, Kelly MG and Li Y WO 2002051832 – reference: Farlow M R and Cummings J L 2007 Am. J. Med.120 388 – reference: Glennon R A, Siripurapu U, Roth B L, Kolanos R, Bondarev M L, Sikazwe D, Lee M and Dukat M 2010 Curr. Top. Med. Chem.10 579 – reference: Maher-Edwards G, Zvartau-Hind M, Hunter A J, Gold M, Hopton G, Jacobs G, Davy M and Williams P 2010 Curr. Alzheimer. Res.7 374 – reference: Arnt J, Bang-Andersen B, Grayson B, Bymaster F P, Cohen M P, DeLapp N W, Giethlen B, Kreilgaard M, McKinzie D L, Neill J C, Nelson D L, Nielsen S M, Poulsen M N, Schaus J M and Witten L M 2010 Int. J. Neuropsychopharmacol.13 1021 – reference: Tsai Y, Dukat M, Slassi A, MacLean N, Demchyshyn L and Savage J E et al. 2000 Bioorg. Med. Chem. Lett.10 2295 – ident: 800_CR11 doi: 10.1016/j.bmcl.2011.05.106 – ident: 800_CR13 doi: 10.1021/jm050247c – ident: 800_CR12 – ident: 800_CR5 doi: 10.1016/S0006-8993(96)01224-3 – ident: 800_CR2 doi: 10.1016/j.ddstr.2004.08.003 – ident: 800_CR8 doi: 10.2174/156720510791383831 – ident: 800_CR14 doi: 10.3987/R-1984-01-0195 – ident: 800_CR7 doi: 10.2174/156802610791111542 – ident: 800_CR15 doi: 10.1038/sj.bjp.0706827 – ident: 800_CR3 doi: 10.1002/gps.938 – ident: 800_CR10 doi: 10.1016/S0960-894X(00)00453-4 – ident: 800_CR4 doi: 10.1016/j.amjmed.2006.08.036 – ident: 800_CR6 doi: 10.1016/S0893-133X(01)00265-2 – ident: 800_CR1 doi: 10.32725/jab.2007.008 – ident: 800_CR9 doi: 10.1017/S1461145710000659 |
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6
receptor (5-HT
6
R) antagonists,... |
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| Title | [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1H-indoles: Synthesis, SAR and biological evaluation as a novel class of 5-HT6 Receptor Antagonists |
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