P3‐296: Safety, tolerability, and pharmacokinetics of a potent and selective 5‐ht<sub>6</sub> receptor antagonist, SUVN‐502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single‐dose pharmacokinetics

Nirogi, Ramakrishna; Mudigonda, Koteshwara; Penta, Kiran Kumar; Bhyrapuneni, Gopinadh; Ajjala, Devender Reddy; Muddana, Nageswararao; Palacharla, Veera Raghava Chowdary; Goyal, Vinod Kumar; Pandey, Santosh Kumar; Abraham, Renny; Jayarajan, Pradeep; Badange, Rajesh Kumar; Kambhampati, Ramasastry

doi:10.1016/j.jalz.2015.06.1669

Cited by 2 publications

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“…In Phase-1 human clinical trial studies, 54 compound 5al showed a favorable safety and pharmacokinetic profile in a single ascending dose in healthy male and female subjects and multiple ascending doses for 14 days in healthy elderly male subjects. Gender and food did not have a significant effect on the pharmacokinetics of compound 5al.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

et al. 2017

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Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HTR) antagonists resulted in identification of 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole dimesylate monohydrate (5al, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HTR (K = 2.04 nM) and selectivity over 100 target sites which include receptors, enzymes, peptides, growth factors, ion channels, steroids, immunological factors, second messengers, and prostaglandins. It has high selectivity over 5-HT receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of 5al, donepezil, and memantine (triple combination) produces synergistic effects in extracellular levels of acetylcholine in the ventral hippocampus. Preclinical efficacy in triple combination and high selectivity over 5-HT receptors are the differentiating features which culminated in selection of 5al for further development. The Phase-1 evaluation of safety and pharmacokinetics has been completed, allowing for the initiation of a Phase-2 proof of concept study.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

et al. 2017

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The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

Khoury

Grysman

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et al. 2018

Expert Opinion on Investigational Drugs

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Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. Areas covered: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. Expert opinion: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

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P3‐296: Safety, tolerability, and pharmacokinetics of a potent and selective 5‐ht₆ receptor antagonist, SUVN‐502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single‐dose pharmacokinetics

Cited by 2 publications

References 0 publications

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

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P3‐296: Safety, tolerability, and pharmacokinetics of a potent and selective 5‐ht6 receptor antagonist, SUVN‐502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single‐dose pharmacokinetics

Cited by 2 publications

References 0 publications

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT6) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

The role of 5 HT6-receptor antagonists in Alzheimer’s disease: an update

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P3‐296: Safety, tolerability, and pharmacokinetics of a potent and selective 5‐ht₆ receptor antagonist, SUVN‐502, following multiple ascending doses in healthy elderly subjects, and effect of gender and food on single‐dose pharmacokinetics

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease

Discovery and Development of 1-[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole Dimesylate Monohydrate (SUVN-502): A Novel, Potent, Selective and Orally Active Serotonin 6 (5-HT₆) Receptor Antagonist for Potential Treatment of Alzheimer’s Disease