RESUMO
Disrupted tau proteostasis and transneuronal spread is a pathological hallmark of Alzheimer's disease. Neurodegenerative diseases remain an unmet medical need and novel disease modifying therapeutics are paramount. Our objective was to develop a mechanistic mathematical model to enhance our understanding of tau antibody pharmacokinetics and pharmacodynamics in animals and humans. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling approach was employed to support the preclinical development and clinical translation of therapeutic antibodies targeting tau for the treatment of Alzheimer's disease. The pharmacokinetics of a tau antibody was evaluated in rat and non-human primate microdialysis studies. Model validation for humans was performed using publicly available clinical data for gosuranemab. In-silico analyses were performed to predict tau engagement in human brain for a range of tau antibody affinities and various dosing regimens. PBPK-PD modeling enabled a quantitative understanding for the relationship between dose, affinity, and target engagement, which supported lead candidate optimization and predictions of clinically efficacious dosing regimens.
RESUMO
The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Triazinas/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/químicaRESUMO
The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
Assuntos
Antipsicóticos/síntese química , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Pirazinas/síntese química , Administração Oral , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , AMP Cíclico/química , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Cães , Feminino , Humanos , Hidrólise , Hipercinese/tratamento farmacológico , Técnicas In Vitro , Isoenzimas/química , Isoenzimas/metabolismo , Ligantes , Masculino , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Conformação Proteica , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteínas Recombinantes/química , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Assuntos
Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores Nicotínicos/metabolismo , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Administração Oral , Animais , Humanos , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacocinética , Conformação Proteica , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Receptores Nicotínicos/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ureia/administração & dosagem , Ureia/farmacocinética , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Hipocampo/metabolismo , Humanos , Córtex Pré-Frontal/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5RESUMO
Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
Assuntos
Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/genética , Estrogênios/agonistas , Estrogênios/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ovariectomia , Fosforilação/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
RATIONALE: Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs. OBJECTIVE: The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident-intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive-compulsive disorder and in a model for evaluating sexual dysfunction. RESULTS: WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar-Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT(2C/2B) receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model. CONCLUSIONS: Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.