sb-742457 and Alzheimer-Disease

Despite the better understanding of the mechanisms underlying Alzheimer's Disease (AD) and launched clinical trials, no AD-modifying treatment based on a synthetic drug has been introduced for almost twenty years. The serotonin 5-HT

Topics: Alzheimer Disease; Animals; Humans; Nootropic Agents; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

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.. 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.. 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.

Topics: Alzheimer Disease; Animals; Benzylamines; Cholinesterase Inhibitors; Cognition; Drug Design; Humans; Indoles; Piperazines; Quinolines; Receptors, Serotonin; Serotonin Antagonists; Sulfones

Alzheimer's disease (AD) is a major neuropsychiatric disorder affecting more than 5 million Americans over age 65. By the year 2050, AD is expected to affect over 30 million. Characterized by neuronal cell death accompanied by the accumulation of neurofibrillary tangles and neuritic plaques, AD results in devastating clinical symptomatology with a lasting psychosocial and financial impact. Studies have shown that the current treatments for AD, cholinesterase inhibitors (ChEI's) and NMDA receptor antagonists, have limited efficacy. The 5-HT-6 receptor antagonists Idalopirdine and Intepirdine have shown the most progress in current clinical trials and warrant consideration as emerging treatments for AD. Areas covered: This review discusses 5-HT6 antagonists currently in clinical trials as potential treatments for AD symptomatology and how 5-HT6 physiology may play a positive role in alleviating AD symptom pathophysiology. A literature search using PubMed was conducted using the terms Idalopirdine, Intepirdine, 5-HT-6 antagonist, and AD as keywords. Clinicaltrials.gov and Alzforum were also used to obtain information on clinical trials. Expert opinion: If current Phase-3 trials are positive, 5-HT6 antagonists such as Idalopirdine and Intepirdine may be considered as supplementary treatments to ChEI's and NMDA receptor antagonists for the symptomatic treatment of AD.

Topics: Aged; Alzheimer Disease; Animals; Benzylamines; Drug Design; Humans; Indoles; Quinolines; Receptors, Serotonin; Serotonin Antagonists; Sulfones

Alzheimer's disease (AD) is one of the most frequent causes of death and disability worldwide and has a significant clinical and socioeconomic impact. In the search for novel therapeutic strategies, serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in AD. This manuscript reviews the compelling evidence for the implication of this receptor in learning and memory processes. We have summarized the current status of the medicinal chemistry of 5-HT6R antagonists and the encouraging preclinical findings that demonstrate their significant procognitive behavioral effects in a number of learning paradigms, probably acting through modulation of multiple neurotransmitter systems and signaling pathways. The results of the ongoing clinical trials are eagerly awaited to shed some light on the validation of 5-HT6R antagonists as a new drug class for the treatment of symptomatic cognitive impairment in AD, either as stand-alone therapy or in combination with established agents.

Topics: Alzheimer Disease; Binding Sites; Clinical Trials as Topic; Cognition Disorders; Humans; Models, Molecular; Molecular Structure; Protein Structure, Tertiary; Receptors, Serotonin; Serotonin Antagonists

To estimate the treatment effects of SB-742457 and donepezil in Alzheimer disease (AD) in a contemporary clinical trial.. Randomized, controlled, parallel-group, exploratory study with a 4-week, single-blind, placebo run-in phase and 24-week, double-blind treatment phase. Primary endpoints were Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog).. One hundred ninety eight subjects with mild-to-moderate probable AD (MMSE scores 12-26) were randomized; 196 were included in the intent-to-treat population (placebo, n = 61; SB-742457 35 mg/day, n = 68; donepezil 10 mg/day, n = 67), and 161 completed. Drug-placebo treatment differences in CIBIC+ score at week 24 were -0.17 (90% confidence interval [CI]: -0.50, 0.16) for SB-742457 and -0.28 (90% CI: -0.61, 0.05) for donepezil. Drug-placebo treatment differences (90% CI) in change from baseline ADAS-Cog score at Week 24 were -0.4 (-2.2, 1.4) for SB-742457 and -1.2 (-3.0, 0.6) for donepezil. All treatments were generally safe and well tolerated.. In this exploratory study, SB-742457 and donepezil were associated with improvements in global function. Treatment effect on cognition for both SB-742457 and donepezil was smaller than those previously observed in previous clinical studies with donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Analysis of Variance; Cholinesterase Inhibitors; Cognition; Donepezil; Female; Humans; Indans; Male; Middle Aged; Piperidines; Quinolines; Serotonin Antagonists; Sulfones

This randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of the 5-HT6 receptor antagonist, SB-742457, in subjects with mild-to-moderate probable Alzheimer's disease (AD).. Participating subjects had a Mini-Mental State Examination (MMSE) score of 12 to 26 after a 4-week, single-blind, placebo run-in phase, and were randomized (2:1:1:2) to receive placebo, SB-742457 5 mg, 15 mg, or 35 mg once daily for 24 weeks. Coprimary efficacy endpoints were the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) score and change from baseline in Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) score at Week 24, in the intent-to-treat (ITT) population. A model-based design provided 90% power to detect a linear trend in treatment response across increasing doses and > or =90% power to compare SB-742457 35 mg with placebo.. 371 subjects were randomized. In the ITT population (n=357), linear trend analysis at Week 24 suggested a dose response for CIBIC+ with a mean slope of -0.05 points/5-mg dose increase (95% confidence interval [CI]: -0.09, -0.01; p=0.016). The dose response slope for change from baseline in ADAS-Cog was -0.22 points/5-mg dose increase (95% CI: -0.45, 0.01; p=0.059). The adjusted mean treatment difference from placebo at Week 24 for SB-742457 35 mg (-0.31) was significant on CIBIC+ (95% CI: -0.62, -0.00; p=0.047) but non-significant on ADAS-Cog (-1.28 [95% CI: -2.96, 0.40]; p=0.135). Adverse events occurred in 24-37% in the SB-742457 groups vs 29% for placebo; 11-16% discontinued SB-742457 vs 15% for placebo.. SB-742457 was generally safe and well tolerated and may be efficacious in AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Quinolines; Receptors, Serotonin; Serotonin Antagonists; Single-Blind Method; Sulfones

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT

Topics: Administration, Oral; Alzheimer Disease; Animals; Drug Discovery; Humans; Indoles; Male; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin Antagonists

Modulators of the serotonin 5-HT6 receptor (5-HT6R) offer a promising strategy for the treatment of the cognitive deficits that are associated with dementia and Alzheimer's disease. Herein, we report the design, synthesis, and characterization of a novel class of 5-HT6R antagonists that is based on the 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to the reference compound, SB-742457, and markedly improved selectivity. Lead optimization led to the identification of (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (14) (Ki = 3 nM and Kb = 0.41 nM). Pharmacological characterization of the 5-HT6R's constitutive activity at Gs signaling revealed that 14 behaved as a neutral antagonist, while SB-742457 was classified as an inverse agonist. Both compounds 14 and SB-742457 reversed phencyclidine-induced memory deficits and displayed distinct procognitive properties in cognitively unimpaired animals (3 mg/kg) in NOR tasks. Compounds 14 and SB-742457 were also active in the Vogel test, yet the anxiolytic effect of 14 was 2-fold higher (MED = 3 mg/kg). Moreover, 14 produced, in a 3-fold higher dose (MED = 10 mg/kg), antidepressant-like effects that were similar to those produced by SB-742457 (MED = 3 mg/kg). Together, these data suggest that the 4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline scaffold is an attractive molecular framework for the development of procognitive agents. The results are promising enough to warrant further detailed mechanistic studies on the therapeutic potential of 5-HT6R antagonists and inverse agonists for the treatment of cognitive decline and depression/anxiety symptoms that are comorbidities of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; CHO Cells; Cognition Disorders; Cricetulus; Cyclic AMP; Disease Models, Animal; HEK293 Cells; Humans; Male; Neuroblastoma; Phencyclidine; Pyrroles; Quinolines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Serotonin; Serotonin Antagonists; Sulfones

Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d).. In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457.. Kinetic analysis of (11)C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo (11)C-GSK215083-specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased.. Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.

Topics: Adult; Alzheimer Disease; Brain Chemistry; Female; Humans; Isotope Labeling; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Quinolines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Reproducibility of Results; Serotonin Antagonists; Sulfones