SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

α7 nicotinic acetylcholine receptor agonists are promising therapeutic candidates for the treatment of cognitive impairment. As a follow up of our internal medicinal chemistry program we investigated a novel series of α7 nAChR agonists. Starting from molecular docking studies on two series of molecules recently developed in our laboratories, an alternative scaffold was designed attempting to combine the optimal features of these previously identified urea and pyrazole compounds. Based on our previous SAR knowledge and on predicted drug-like properties, a small library was synthesized in parallel manner, affording compounds with excellent α7 nAChR activity, selectivity and preliminary ADME profile.

OBJECTIVE: To qualify reductions in dopamine transporter (DAT) levels assessed by SPECT as an enrichment biomarker for Parkinson's disease (PD) clinical trials.

Alpha-7 nicotinic acetylcholine receptors (α7 nAChR) are implicated in the modulation of many cognitive functions such as attention, working memory, and episodic memory. For this reason, α7 nAChR agonists represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort, around our previously reported chemical series, permitted the discovery of a novel class of α7 nAChR agonists with improved selectivity, in particular against the α3 receptor subtype and better ADME profile. The exploration of this series led to the identification of 5-(4-acetyl[1,4]diazepan-1-yl)pentanoic acid [5-(4-methoxyphenyl)-1H-pyrazol-3-yl] amide (25, SEN15924, WAY-361789), a novel, full agonist of the α7 nAChR that was evaluated in vitro and in vivo. Compound 25 proved to be potent and selective, and it demonstrated a fair pharmacokinetic profile accompanied by efficacy in rodent behavioral cognition models (novel object recognition and auditory sensory gating).

Several anti-amyloid β (Aβ) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aβ antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aβ plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aβ plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble Aβ species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of Aβ1–42 and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble Aβ moieties. Importantly C-terminal anti-Aβ antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-Aβ antibodies effectively interact with both soluble and insoluble forms of Aβ and therefore appear particularly well suited for testing the Aβ hypothesis of AD.

On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a new class of 2-(pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(2H)-one derivatives (3-50) were synthesized and evaluated as potent H(3) receptor antagonists. In particular, compound 39 exhibited potent in vitro binding and functional activities at the H(3) receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile.

α7 Nicotinic acetylcholine receptors (α7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the α7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models.

The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.

Many of the cognitive deficits seen in Alzheimer's disease (AD), result from progressive loss of cholinergic neurons, and may be mimicked in healthy volunteers by administration of the muscarinic receptor antagonist, scopolamine, which produces a transient cholinergic blockade. The clinical relevance and the predictive value of the scopolamine model are supported by the fact that donepezil can reverse scopolamine-induced deficits in healthy subjects. Selective 5-HT6 receptor antagonists, which indirectly modulate cholinergic and glutaminergic tone in relevant brain regions, may be able to similarly reverse scopolamine-induced deficits and thereby provide a mechanistic signal. Randomized, double-blind, placebo-controlled 5-way crossover study to evaluate the effect of a single dose of SAM-760 (5, 20 or 60 mg), donepezil (10 mg; positive control) or placebo on scopolamine (0.5mg) induced psychomotor and cognitive deficits in 30 young healthy adults. A computerized battery of neuropsychological tests (CogState) was administered during each crossover period; the key outcome measure was the Groton Maze Learning Task (GMLT). In addition to safety, exploratory phamacodynamic (PD) and pharmacokinetic (PK) measures were also assessed. The cognitive test battery was well tolerated and subject performance met standards of data integrity. Within-subject variability in performance on the battery was consistent with previous studies. There was a significant learning effect, but the carryover effect was not significant. Peak effect of scopolamine occurred 1–3 hours -postdose. Donepezil partially reversed cognitive deficits on most but not all measures of the battery. None of the SAM-760 doses were able to significantly ameliorate the effects of scopolamine. All study drug treatments received in the trial were well-tolerated with the exception of one SAE of mood disorders with suicidal ideation occurring in the donepezil cohort. A dose of 0.5mg scopolamine induced comprehensive cognitive impairment in healthy young subjects as anticipated. A single 10mg dose of donepezil ameliorated the majority of these effects, whereas SAM-760, at the evaluated doses, did not demonstrate an effect. 5-HT6 antagonism by itself may be insufficient to ameliorate a profound cholinergic deficit. Alternatively, chronic dosing with a 5-HT6 antagonist may be required to effect a change in such an experimental scopolamine model.

On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.

RATIONALE:α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.OBJECTIVES:We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.METHODS:Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.RESULTS:WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.CONCLUSIONS:These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.

Preclinical and preliminary clinical studies suggest that blocking 5 hydroxytrypamine receptors[5-HT6R] improves cognition and promotes synaptic plasticity by releasing acetylcholine and glutamate. Alzheimer's disease (AD) is partly characterized by deficits in these neurotransmitters. Antagonism of 5-HT6R, specifically brain localized, may result in less peripheral side effects than existing AD treatments. Ascending single oral doses 0.25-70 mg SAM-760 were administered to young subjects and multiple doses 1.5-30 mg and 10-20 mg to young and elderly subjects, respectively, using a randomized, double-blind, sponsor un-blinded, placebo-controlled, sequential dose study design. Additional cohorts in the SAD study included: elderly (10 mg SAM-760), food effect (10 mg SAM-760) and ketoconazole interaction (5 mg SAM-760; 400 mg ketoconazole). Study assessments consisted of safety, tolerability SAM-760 pharmacokinetics (plasma and urine). SAM-760 was safe and well tolerated as a single oral dose up to 70 mg in young subjects, at 10 mg in elderly and as multiple oral doses (QD 14 days) up to 30 mg and 20 mg in young and elderly subjects, respectively. There were no dose-limiting adverse events (AE). The most frequently reported treatment emergent AEs was headache. There were no subjects withdrawn for safety reasons, serious adverse events or deaths. SAM-760 exhibited dose proportional increases in Cmax and AUC0-INF for single doses up to 60 mg (young). Mean accumulation was 3.2-fold for AUC0-TAU and 2.7-fold for Cmax after 14-days of daily dosing, with approximate steady state exposure being reached following 7-days. SAM-760 elimination was similar in young and elderly subjects (t1/2 of approximately 32 hr) . Co-administration of ketoconazole with a single dose of SAM-760 increased AUC0-INF and Cmax, by 38% and 32%, respectively. There was no detectable PK food effect. SAM-760 was safe and well tolerated as a single and multiple oral dose over the dose ranges tested in healthy young and elderly subjects. SAM-760 exhibits linear PK for single doses up to 60 mg, with an accumulation of approximately 3-fold following multiple dose administration. SAM-760 elimination was comparable between healthy young and elderly subjects.