Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists

Liu, Kevin G.; Robichaud, Albert J.; Greenfield, Alexander; Lo, Jennifer R.; Grosanu, Cristina; Mattes, James F.; Cai, Yanxuan; Zhang, Guo Ming; Zhang, Jean Y.; Kowal, Dianne; Smith, Deborah L.; Di, Li; Kerns, Edward H.; Schechter, Lee E.; Comery, Thomas A.

doi:10.1016/j.bmc.2010.10.033

Cited by 21 publications

(11 citation statements)

References 21 publications

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“…A dataset of 223 5-HT 6 receptor ligands with K i experimental values were collected from the continued efforts of Wyeth Research [14–21]. The corresponding p K i (−log K i ) values which were converted from the binding affinity K i values, were used as the dependent variables in the 3D-QSAR analyses.…”

Section: Materials and Experimental Methodsmentioning

confidence: 99%

“…To clarify the role of 5-HT 6 receptor in the central nervous system, currently, more and more potent 5-HT 6 ligands were synthesized such as MS-245 [12], 4′-amino derivative of MS-245 [13], a series of ligands synthesized at Wyeth Research, most of which comprised of heterocyclic core with a basic amine and an arylsulfonyl moiety [14–21] and others [2,22–24]. Several studies indicate that 5-HT 6 ligands may be cognition enhancers; however, not all studies have come up with the similar result [25].…”

Section: Introductionmentioning

confidence: 99%

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Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

Ming

et al. 2011

IJMS

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5-HT6 receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT6 ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT6 ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistical results with r2ncv, q2 values of 0.85 and 0.50 for CoMFA, 0.81 and 0.53 for CoMSIA, respectively. Their predictive powers were validated by external test set, showing r2pred of 0.71 and 0.76. The contour maps also provide a visual representation of contributions of steric, electrostatic, hydrophobic and hydrogen bond fields as well as the prospective binding models. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential 5-HT6 ligands.

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Section: Materials and Experimental Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

Ming

et al. 2011

IJMS

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“…For biological activities of the indazole moiety, see: Ali et al (2012); Abbassi et al (2012); Plescia et al (2010); Lee et al (2001); Liu et al (2011). For related compounds, see: Kouakou et al (2013); Chicha et al (2013).…”

Section: Related Literaturementioning

confidence: 99%

“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: PLATON (Spek, 2009) and publCIF (Westrip, 2010). Indazole moiety have been nucleus is a pharmaceutically important and emerging heterocycle with a broad spectrum of activities including anti-microbial1, anti-cancer, anti-inflammatory, anti-platelet, and selective 5-HT6 antagonists (Ali et al, 2012;Abbassi et al, 2012;Plescia et al, 2010;Lee et al, 2001;Liu et al, 2011). The present work is a continuation of the investigation on the indazole derivatives published recently by our team (Kouakou et al, 2013;Chicha et al, 2013).…”

Section: Data Collectionmentioning

confidence: 99%

6,6′-Dinitro-1,1′-(ethane-1,2-diyl)di(1H-indazole)

et al. 2014

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The molecule of the title compound, C16H12N6O4, is built up from two fused five- and six-membered rings linked by an ethylene group. The dihedral angle between the planes through the indazole ring systems is 39.74 (5)°. The nitro groups are tilted by 7.2 (2) and 8.5 (2)° with respect to planes of the fused-ring systems. In the crystal, molecules are linked by C—H...N and C—H...O hydrogen bonds into chains running parallel to thecaxis.

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“…1,4,5 Some VNS products are useful starting materials for the synthesis of biologically active compounds, like recently reported potent and selective 5-HT6 antagonists. 6 We employed such VNS products to the synthesis of indazole and condensed pyrazole derivatives that showed promising anticancer activity and were screened for…”

Section: Introductionmentioning

confidence: 99%

On the reactions of tertiary carbanions with some nitroindazoles and nitrobenzotriazoles

Bernard¹,

Kujawski²,

Skierska³

et al. 2012

Arkivoc

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The vicarious nucleophilic substitution in some nitroindazole and nitrobenzotriazole derivatives with tertiary carbanions leads almost exclusively to products substituted para to the nitro group. As results from the theoretical calculations and structural evidences, such reaction outcome is due mainly to the stereoelectronic reasons in combination with the considerable shortening of the Cortho-CNO2 bond. The presence of the chiral and prochiral centres (the methine and Nmethylene groups, respectively) often gives rise to additional splitting of the methylene protons signal that is transmitted on a long distance provided there is no pyridinic nitrogen in the pathway of coupling.

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Identification of 3-sulfonylindazole derivatives as potent and selective 5-HT6 antagonists

Cited by 21 publications

References 21 publications

Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

Investigation of the Structure Requirement for 5-HT6 Binding Affinity of Arylsulfonyl Derivatives: A Computational Study

6,6′-Dinitro-1,1′-(ethane-1,2-diyl)di(1H-indazole)

On the reactions of tertiary carbanions with some nitroindazoles and nitrobenzotriazoles

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