RESUMO
Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 µM. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia.
Assuntos
Azepinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Sono/efeitos dos fármacos , Triazóis/farmacologia , Animais , Área Sob a Curva , Azidas , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Eletrocardiografia , Eletromiografia , Humanos , Macaca mulatta , Atividade Motora/efeitos dos fármacos , Octreotida/análogos & derivados , Receptores de Orexina , Ligação Proteica/efeitos dos fármacos , Ratos , Tempo de Reação/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , TransfecçãoRESUMO
A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.
Assuntos
Amidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Animais , Camundongos , Ratos , Ratos WistarRESUMO
T-type calcium channels have been implicated in many behaviorally important neurophysiological processes, and altered channel activity has been linked to the pathophysiology of neurological disorders such as insomnia, epilepsy, Parkinson's disease, depression, schizophrenia, and pain. We have previously identified a number of potent and selective T-type channel antagonists (Barrow et al., 2007; Shipe et al., 2008; Yang et al., 2008). Here we describe the properties of the antagonist TTA-A2 [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl}ethyl)acetamide], assessed in patch-clamp experiments. TTA-A2 blocks T-type channels (Ca(v)3.1, 3.2, 3.3) voltage dependently and with high potency (IC(50) â¼100 nM). Stimulation at 3 Hz revealed additional use dependence of inhibition. A hyperpolarized shift of the channel availability curve and delayed channel recovery from inactivation suggest that the compound preferentially interacts with and stabilizes inactivated channels. The compound showed a â¼300-fold selectivity for Ca(v)3 channels over high-voltage activated calcium channels. Inhibitory effects on native T-type currents were confirmed in brain slice recordings from the dorsal lateral geniculate nucleus and the subthalamic nucleus. Furthermore, we demonstrate that in vivo T-type channel inhibition by TTA-A2 suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Ca(v)3.1 and Ca(v)3.3, suggesting the selective effect of TTA-A2 on recurrent thalamocortical network activity. The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.
Assuntos
Nível de Alerta/efeitos dos fármacos , Benzenoacetamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Piridinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Benzenoacetamidas/química , Benzenoacetamidas/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/genética , Linhagem Celular , Clonagem Molecular , Relação Dose-Resposta a Droga , Corpos Geniculados/efeitos dos fármacos , Corpos Geniculados/metabolismo , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Piridinas/química , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transtornos do Despertar do Sono/tratamento farmacológico , Transtornos do Despertar do Sono/metabolismoRESUMO
The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Quinazolinonas/química , Quinazolinonas/farmacologia , Animais , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Cromatografia Líquida de Alta Pressão , Descoberta de Drogas , Haplorrinos , Humanos , Quinazolinonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.
Assuntos
Alcanos/farmacologia , Descoberta de Drogas , Hipnóticos e Sedativos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Alcanos/química , Alcanos/farmacocinética , Animais , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Eletroencefalografia , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Receptores de Orexina , Ratos , Ratos Sprague-DawleyRESUMO
Orexin (hypocretin) neuropeptides promote wakefulness by signaling through two G-protein coupled receptors, Orexin 1 Receptor (OX(1)R) and Orexin 2 Receptor (OX(2)R). MK-6096 is an orally bioavailable potent and selective reversible antagonist of OX(1)R and OX(2)R currently in clinical development for insomnia. In radioligand binding and functional cell based assays MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel of >170 receptors and enzymes. MK-6096 occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM, and dose-dependently reduced locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). DORA-22, an analog of MK-6096, exhibits similar sleep promoting properties that are absent OX(1/2)R double knockouts, demonstrating the mechanism of action and specificity of these effects. These findings with a novel, structurally distinct class of OxR antagonists provide further validation of the orexin pathway as an effective target to promote normal sleep. Comparative analysis of the biochemical and pharmacokinetic properties of these compounds relative to other OXR antagonists provides a basis for understanding the attributes critical for in vivo efficacy. This mechanism is distinct from current standard of care such that MK-6096 represents a novel and selective therapeutic for the treatment of insomnia. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Assuntos
Piperidinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Animais , Cães , Camundongos , Receptores de Orexina , RatosRESUMO
TWIK-related acid-sensitive K(+) (K(2P) 9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.
Assuntos
Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , Animais , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Ratos Sprague-Dawley , Sono/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexinâ 1 and orexinâ 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional inâ vivo activity in preclinical sleep models, and has advanced into phaseâ II clinical trials for the treatment of insomnia.
Assuntos
Hipnóticos e Sedativos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/síntese química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Descoberta de Drogas , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Vigília/efeitos dos fármacosRESUMO
Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicates that the amplitudes of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen in wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveals increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug's action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action.
Assuntos
Antidepressivos de Segunda Geração/farmacologia , Nível de Alerta/fisiologia , Ritmo Circadiano/fisiologia , Fluoxetina/farmacologia , Canais de Potássio/metabolismo , Sono REM/fisiologia , Animais , Comportamento Animal/fisiologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Análise por Pareamento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes Neurológicos , Fenótipo , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/genéticaRESUMO
Orexin is a key neurotransmitter of central arousal and reward circuits in the CNS. Two receptors respond to orexin signaling, Orexin 1 Receptor (OX1R) and Orexin 2 Receptor (OX2R) with partially overlapping brain distributions. Genetic and pharmacological studies suggest orexin receptor antagonists could provide therapeutic benefit for insomnia and other disorders in which sleep/wake cycles are disrupted. Preclinical data has also emerged showing that the orexin system is involved in the behavioral and neurological effects of drugs of abuse (Aston-Jones et al., 2009; Harris et al., 2005). Here we report sleep promoting effects of a recently described small molecule dual orexin receptor OX1R and OX2R antagonist. This dual orexin receptor antagonist (DORA) also inhibits the ability of subchronic amphetamine to produce behavioral sensitization measured 10 days following pre-treatment. Transcriptional profiling of isolated reward and arousal circuits from brains of behaviorally sensitized animals showed that the DORA blocked the significant alteration of gene expression levels in response to amphetamine exposure, particularly those associated with synaptic plasticity in the VTA. Further, DORA attenuates the ability of nicotine to induce reinstatement of extinguished responding for a reinforcer, demonstrating selectivity of the effect to reward pathways and not to food intake. In summary, these data demonstrate efficacy of a dual orexin receptor antagonist for promotion of sleep and suggest that pharmacological inhibition of the orexin system may play a role in both prevention of drug-induced plasticity and drug-relapse.
Assuntos
Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Oligopeptídeos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Anfetamina/farmacologia , Análise de Variância , Animais , Benzimidazóis/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Perfilação da Expressão Gênica/métodos , Masculino , Atividade Motora/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Receptores de Orexina , Prolina/análogos & derivados , Prolina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Sono/efeitos dos fármacos , Transcrição Gênica/genética , Área Tegmentar Ventral/anatomia & histologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Assuntos
Azepinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Triazóis/farmacologia , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Receptores de Orexina , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Telemetria , Triazóis/síntese química , Triazóis/farmacocinética , Vigília/efeitos dos fármacosRESUMO
A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervous system efficacy in epilepsy and tremor models, as well as significant effects on rat active wake as measured by electrocorticogram.
RESUMO
The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking CaV3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet-induced weight gain, without changes in food intake or sensitivity to high-fat diet-induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet-induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Gorduras na Dieta/antagonistas & inibidores , Aumento de Peso/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo T/deficiência , Canais de Cálcio Tipo T/genética , Gorduras na Dieta/farmacologia , Masculino , Camundongos , Camundongos Knockout , Estrutura Molecular , RatosRESUMO
Low-voltage-activated (T-type) calcium channels play a role in diverse physiological responses including neuronal burst firing, hormone secretion, and cell growth. To better understand the biological role and therapeutic potential of the target, a number of structurally diverse antagonists have been identified. Multiple drug interaction sites have been identified for L-type calcium channels, suggesting a similar possibility exists for the structurally related T-type channels. Here, we radiolabel a novel amide T-type calcium channel antagonist (TTA-A1) and show that several known antagonists, including mibefradil, flunarizine, and pimozide, displace binding in a concentration-dependent manner. Further, we identify a novel quinazolinone T-type antagonist (TTA-Q4) that enhanced amide radioligand binding, increased affinity in a saturable manner and slowed dissociation. Functional evaluation showed these compounds to be state-dependent antagonists which show a positive allosteric interaction. Consistent with slowing dissociation, the duration of efficacy was prolonged when compounds were co-administered to WAG/Rij rats, a genetic model of absence epilepsy. The development of a T-type calcium channel radioligand has been used to demonstrate structurally distinct TTAs interact at allosteric sites and to confirm the potential for synergistic inhibition of T-type calcium channels with structurally diverse antagonists.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/química , Células Cultivadas , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
Assuntos
Azepinas/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Azepinas/farmacocinética , Azepinas/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Receptores de Orexina , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Desenho de Fármacos , Piperidinas/síntese química , Piperidinas/farmacologia , Piranos/síntese química , Piranos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/química , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Frequência Cardíaca/efeitos dos fármacos , Modelos Animais , Estrutura Molecular , Piperidinas/química , Piranos/química , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of a novel series of potent and selective T-type calcium channel antagonists is reported. Initial optimization of high-throughput screening leads afforded a 1,4-substituted piperidine amide 6 with good potency and limited selectivity over hERG and L-type channels and other off-target activities. Further SAR on reducing the basicity of the piperidine and introducing polarity led to the discovery of 3-axial fluoropiperidine 30 with a significantly improved selectivity profile. Compound 30 showed good oral bioavailability and brain penetration across species. In a rat genetic model of absence epilepsy, compound 30 demonstrated a robust reduction in the number and duration of seizures at 33 nM plasma concentration, with no cardiovascular effects at up to 5.6 microM. Compound 30 also showed good efficacy in rodent models of essential tremor and Parkinson's disease. Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/química , Sistema Cardiovascular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Piperidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
People with developmental disabilities sleep less and experience higher incidence of clinical sleep disorders than the general population. Exploring the neurophysiology linking sleep with daytime performance in patients with developmental disabilities is now possible using minimally sufficient sleep and sleep-sensitive behavioral assays. Although frequent sampling represents the primary difficulty, it is required to untangle coincident effects of sleep quality amidst circadian variation. Recent evidence finds high quality sleep promotes brain plasticity, improves health measures, and enriches quality of life. Sleep treatments for apnea, insomnia, restless limbs, and conditioned sleep-aversion are available, although not readily provided, for people with developmental disabilities. This population would gain both clinical and behavioral benefits as improved sleep-monitoring, behavioral testing, and sleep-treatment technology is adapted to their needs.