Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents

Holenz, Jörg; Pauwels, Petrus J.; Dı́az, José Luis; Mercè, Ramon; Codony, Xavier; Buschmann, Helmut

doi:10.1016/j.drudis.2006.02.004

Cited by 145 publications

(89 citation statements)

References 65 publications

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“…1). 6 SB-742457 developed by GlaxoSmithKline is in the phase II clinical trial for the treatment of cognitive dysfunction associated with Alzheimer's disease. The Lilly compound LY-483518 is also in the phase II clinical trial for the treatment of cognitive impairment associated with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…The Lilly compound LY-483518 is also in the phase II clinical trial for the treatment of cognitive impairment associated with schizophrenia. 6 SB-271046 is in the phase I clinical trial, developed by GlaxoSmithKline and also for the treatment of Alzheimer's disease and schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

“…6 As a part of our ongoing project to develop 5-HT6 receptor antagonists, we designed, synthesized and biologically evaluated arylsulfonylpiperazine derivatives 1-3 as novel 5-HT6 receptor ligands (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

2007

Bulletin of the Korean Chemical Society

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The 5-HT6 antagonists are mainly related to the treatment of cognitive dysfunction or impairment associated with Alzheimer's disease and schizophrenia. There have been lots of efforts to develop 5-HT6 antagonists. As in our efforts, arylsulfonylpiperazine derivatives 1-3 were designed, synthesized and biologically evaluated against the human recombinant 5-HT6 serotonin receptor. Total 36 compounds were synthesized and the most active compound among the synthesized compounds is compound 2h with an IC50 value of 1.5 μM. The compound 2h is novel as 5-HT6 receptor ligand and could act as lead for the novel 5-HT6 receptor ligands.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

2007

Bulletin of the Korean Chemical Society

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“…Thus, 5-HT6R antagonists could be of great therapeutic value in the treatment of cognitive disorders where deficits in episodic memory are a major feature, including aging, Alzheimer's disease, and schizophrenia. Interestingly, 5-HT6R antagonists such as LY-483518, SB-742457, and PRX-07034 have already entered clinical trials for the treatment of cognitive impairment associated with Alzheimer's disease and schizophrenia, and other antagonists are under active development (Holenz et al, 2006;www.epixmed.com).…”

Section: -Ht6r Blockade Improves Memory V Da Silva Costa Et Almentioning

confidence: 99%

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Costa

Duchatelle²,

Boulouard³

et al. 2008

Neuropsychopharmacol

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Studies have recently suggested that blockade of 5-HT6 receptors (5-HT6R) improves memory processes. As episodic memory alteration is one of the first deficits observed during normal aging and in neurological and neuropsychiatric disorders (Alzheimer's disease, schizophrenia), the present study sought to characterize the effects of 5-HT6R blockade on spatial recognition memory, which can be considered as 'episodic-like' memory, in rodents. We quantified the effects of the selective 5-HT6R antagonist SB-271046 (10 mg/kg, i.p.), using the two-trial place recognition task in the Y-maze, on acquisition, consolidation, and retrieval of spatial recognition memory in young adult mice (6-week-old; intertrial intervals (ITIs) 30, 60, 120, 240, and 360 min) and on the consolidation of spatial recognition memory in aged mice (3-, 12-, 18-, and 21-month-old; ITI 60 and 240 min). SB-271046-treated young adult mice explored the new arm more after a 240-min (pre-acquisition) and 360-min (post-acquisition) ITI, whereas vehicle-treated animals failed to discriminate the new arm when the ITI exceeded 120 min (pre-acquisition) or 240 min (post-acquisition). Aged mice, which expressed spatial memory deficits, explored the new arm more after a 60-min ITI (21-month-old) and a 240-min ITI (18-and 21-month-old) when treated with SB-271046. Consequently, 5-HT6R blockade improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory. This study provides further support for the use of 5-HT6R antagonists in the treatment of episodic memory disorders related to aging as well as neurological disorders such as Alzheimer's disease and schizophrenia.

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“…Along with this, several studies have been published reporting an association of 5-HT 6 receptor variants with neuropsychological and neuropsychiatric diseases such as schizophrenia [9][10][11][12][13] , bipolar affective disorders 14 , Parkinson's disease 15 or Alzheimer's disease [16][17][18] and the treatment of obesity and related metabolic disorders. Therefore, 5-HT 6 receptors represent an extremely attractive target for the development of novel small molecule therapeutics for the treatment of various neurodegenerative disorders [19][20][21] . Many 5-HT 6 receptor ligands have been reported and some of the clinically advancing molecules include SAM-760 from Pfizer, SB-742457 ( Figure 1) from GSK is in Phase II clinical trials for dementia as per their product development pipeline published 22,23 in February 2013.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT₆receptor antagonists

Nirogi

Bandyala

Reballi

et al. 2014

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of N 0 -[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl ethane-1,2-diamines and N 0 -[3-(indole-1-sulfonyl) aryl]-N,N-dimethyl propane-1,3-diamines was designed and synthesized as 5-HT 6 receptor ligands. These compounds, when screened in a functional reporter gene-based assay, displayed potent antagonistic activity with K b values in the range of 1.8-60 nM. The lead compound 9y has shown good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. It was selected for detailed profiling.

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Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents

Cited by 145 publications

References 65 publications

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT₆receptor antagonists

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Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents

Cited by 145 publications

References 65 publications

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT6Receptor Ligands

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT6Receptor Ligands

Selective 5-HT6 Receptor Blockade Improves Spatial Recognition Memory and Reverses Age-Related Deficits in Spatial Recognition Memory in the Mouse

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT6receptor antagonists

Contact Info

Product

Resources

About

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

Synthesis and Biological Evaluation of Arylsulfonylpiperazine Derivatives as 5-HT₆Receptor Ligands

Design, synthesis and pharmacological evaluation of indolylsulfonamide amines as potent and selective 5-HT₆receptor antagonists