Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer’s disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer’s type

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer’s disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer’s type

Effect of masupirdine (SUVN‐502) on cognition in patients with moderate Alzheimer's disease: A randomized, double‐blind, phase 2, proof‐of‐concept study

Abstract Introduction This study explored the efficacy and safety of a serotonin‐6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine. Methods The effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty‐seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2‐ to 4‐week screening period, the study consisted of a 26‐week double‐blind treatment period, and a 4‐week washout period. The primary efficacy measure was the 11‐item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale–Sum of Boxes, Mini‐Mental State Examination, 23‐item Alzheimer's Disease Co‐operative Study Activities of Daily Living, and 12‐item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305). Results The MMRM results showed statistically non‐significant treatment differences in change from baseline in ADAS‐Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations. Discussion Masupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed. Highlights Masupirdine was evaluated in moderate Alzheimer's disease patients. First trial in class with background treatment of donepezil and memantine. Masupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed

Large scale changes in the transcriptome of Eisenia fetida during regeneration.

Earthworms show a wide spectrum of regenerative potential with certain species like Eisenia fetida capable of regenerating more than two-thirds of their body while other closely related species, such as Paranais litoralis seem to have lost this ability. Earthworms belong to the phylum Annelida, in which the genomes of the marine oligochaete Capitella telata and the freshwater leech Helobdella robusta have been sequenced and studied. Herein, we report the transcriptomic changes in Eisenia fetida (Indian isolate) during regeneration. Following injury, E. fetida regenerates the posterior segments in a time spanning several weeks. We analyzed gene expression changes both in the newly regenerating cells and in the adjacent tissue, at early (15days post amputation), intermediate (20days post amputation) and late (30 days post amputation) by RNAseq based de novo assembly and comparison of transcriptomes. We also generated a draft genome sequence of this terrestrial red worm using short reads and mate-pair reads. An in-depth analysis of the miRNome of the worm showed that many miRNA gene families have undergone extensive duplications. Sox4, a master regulator of TGF-beta mediated epithelial-mesenchymal transition was induced in the newly regenerated tissue. Genes for several proteins such as sialidases and neurotrophins were identified amongst the differentially expressed transcripts. The regeneration of the ventral nerve cord was also accompanied by the induction of nerve growth factor and neurofilament genes. We identified 315 novel differentially expressed transcripts in the transcriptome, that have no homolog in any other species. Surprisingly, 82% of these novel differentially expressed transcripts showed poor potential for coding proteins, suggesting that novel ncRNAs may play a critical role in regeneration of earthworm

Design, Synthesis, and Pharmacological Evaluation of Piperidin-4-yl amino aryl sulfonamides: Novel, Potent, Selective, Orally Active, and Brain Penetrant 5‑HT₆ Receptor Antagonists

Our initial findings around aryl sulfonamide series led to <i>N</i>-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT₆ receptor (5-HT₆R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT₆R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability. Several structural modifications including bringing conformational constraint around the sulfonamide −NH group and introduction of a heteroatom to modulate the physicochemical properties were attempted. This effort culminated in the discovery of series of novel, potent, selective, orally bioavailable, and adequately brain penetrant compounds with no hERG liability. These compounds showed activity in animal models of cognition like object recognition task and water maze and in brain microdialysis studies at lower doses

Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5‑HT₄ Receptor Partial Agonists

Alzheimer’s disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT₄ receptor (5-HT₄R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT₄R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure–activity relationships, compound <b>4o</b> was identified as a potent 5-HT₄R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT₄R antagonist, attenuated the activity of compound <b>4o</b> in the novel-object-recognition-test cognition model

Synthesis, Structure–Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5‑HT₄ Receptor Partial Agonists

Alzheimer’s disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT₄ receptor (5-HT₄R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT₄R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure–activity relationships, compound <b>4o</b> was identified as a potent 5-HT₄R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT₄R antagonist, attenuated the activity of compound <b>4o</b> in the novel-object-recognition-test cognition model

Discovery and Development of 1‑[(2-Bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)methyl]‑1<i>H</i>‑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

Optimization of a novel series of 3-(piperazinylmethyl) indole derivatives as 5-hydroxytryptamine-6 receptor (5-HT₆R) antagonists resulted in identification of 1-[(2-bromophenyl)­sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl)­methyl]-1<i>H</i>-indole dimesylate monohydrate (<b>5al</b>, SUVN-502) as a clinical candidate for potential treatment of cognitive disorders. It has high affinity at human 5-HT₆R (<i>K</i>_i = 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_2A receptor. It is orally bioavailable and brain penetrant with robust preclinical efficacy. The combination of <b>5al</b>, 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_2A receptors are the differentiating features which culminated in selection of <b>5al</b> 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