RESUMO
A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1â¯mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle.
Assuntos
Compostos Bicíclicos com Pontes/metabolismo , Cicloexanos/metabolismo , Compostos Heterocíclicos/metabolismo , Compostos Bicíclicos com Pontes/química , Cicloexanos/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Selective activation of the M1 muscarinic acetylcholine receptor (mAChR) via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. Herein, we describe the characterization of an M1 PAM radioligand, 8-((1S,2S)-2-hydroxycyclohexyl)-5-((6-(methyl-t3)pyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one ([(3)H]PT-1284), as a tool for characterizing the M1 allosteric binding site, as well as profiling novel M1 PAMs. 8-((1S,2S)-2-Hydroxycyclohexyl)-5-((6-methylpyridin-3-yl)methyl)-8,9-dihydro-7H-pyrrolo[3,4-hour]quinolin-7-one (PT-1284 ( 1: )) was shown to potentiate acetylcholine (ACh) in an M1 fluorometric imaging plate reader (FLIPR) functional assay (EC50, 36 nM) and carbachol in a hippocampal slice electrophysiology assay (EC50, 165 nM). PT-1284 ( 1: ) also reduced the concentration of ACh required to inhibit [(3)H]N-methylscopolamine ([(3)H]NMS) binding to M1, left-shifting the ACh Ki approximately 19-fold at 10 µM. Saturation analysis of a human M1 mAChR stable cell line showed that [(3)H]PT-1284 bound to M1 mAChR in the presence of 1 mM ACh with Kd, 4.23 nM, and saturable binding capacity (Bmax), 6.38 pmol/mg protein. M1 selective PAMs were shown to inhibit [(3)H]PT-1284 binding in a concentration-responsive manner, whereas M1 allosteric and orthosteric agonists showed weak affinity (>30 µM). A strong positive correlation (R(2) = 0.86) was found to exist between affinity values generated for nineteen M1 PAMs in the [(3)H]PT-1284 binding assay and the EC50 values of these ligands in a FLIPR functional potentiation assay. These data indicate that there is a strong positive correlation between M1 PAM binding affinity and functional activity, and that [(3)H]PT-1284 can serve as a tool for pharmacological investigation of M1 mAChR PAMs.
Assuntos
Isoindóis/metabolismo , Piridinas/metabolismo , Ensaio Radioligante , Receptor Muscarínico M1/metabolismo , Acetilcolina , Regulação Alostérica , Animais , Autorradiografia , Células CHO , Cricetinae , Cricetulus , Fenômenos Eletrofisiológicos , Fluorometria , Células HEK293 , Hipocampo/fisiologia , Humanos , Cinética , Masculino , Membranas/metabolismo , N-Metilescopolamina/metabolismo , Tomografia por Emissão de Pósitrons , Ratos Sprague-DawleyRESUMO
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Indóis/química , Indóis/farmacologia , Receptor Muscarínico M1/metabolismo , Amidas/farmacocinética , Animais , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Indóis/farmacocinética , Camundongos , Simulação de Acoplamento Molecular , Receptor Muscarínico M1/agonistasRESUMO
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic. Thus, it is critical to define carefully a potentiator's mechanism-based therapeutic index (TI) and to determine confidently its translatability from rodents to higher-order species. Accordingly, the novel AMPAR potentiator N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) was characterized in a series of in vitro assays and single-dose animal studies evaluating AMPAR-mediated activities related to cognition and safety to afford an unbound brain compound concentration (Cb,u)-normalized interspecies exposure-response relationship. Because it is unknown which AMPAR subtype(s) may be selectively potentiated for an optimal TI, PF-4778574 binding affinity and functional potency were determined in rodent tissues expected to express a native mixture of AMPAR subunits and their associated proteins to afford composite pharmacological values. Functional activity was also quantified in recombinant cell lines stably expressing human GluA2 flip or flop homotetramers. Procognitive effects of PF-4778574 were evaluated in both rat electrophysiological and nonhuman primate (nhp) behavioral models of pharmacologically induced N-methyl-d-aspartate receptor hypofunction. Safety studies assessed cerebellum-based AMPAR activation (mouse) and motor coordination disruptions (mouse, dog, and nhp), as well as convulsion (mouse, rat, and dog). The resulting empirically derived exposure-response continuum for PF-4778574 defines a single-dose-based TI of 8- to 16-fold for self-limiting tremor, a readily monitorable clinical adverse event. Importantly, the Cb,u mediating each physiological effect were highly consistent across species, with efficacy and convulsion occurring at just fractions of the in vitro-derived pharmacological values.
Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA/agonistas , Receptores de AMPA/fisiologia , Tiofenos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Células Cultivadas , Cães , Agonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Tiofenos/uso terapêutico , Resultado do TratamentoRESUMO
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Assuntos
Carbamatos/química , Oxazolidinonas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/química , Esquizofrenia/tratamento farmacológico , Administração Oral , Regulação Alostérica , Sítio Alostérico , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Oxazolidinonas/químicaRESUMO
Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, the efficacy of which is thought to be mediated through co-activation of the M1 and M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to the actions of selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5'-cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation in the striatum, hippocampus, and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats using ex vivo recordings from CA1 (Cornu Ammonis 1) as well as in vivo hippocampal theta. As expected, xanomeline's effects across these readouts were consistent with activation of both M1 and M4 mAChRs; however, differences were observed across different brain regions, suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite having nearly equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was driven, in part, through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR.
Assuntos
Hipocampo/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piridinas/farmacologia , Receptor Muscarínico M1/metabolismo , Tiadiazóis/farmacologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismoRESUMO
It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.
RESUMO
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
Assuntos
Regulação Alostérica , Compostos Azabicíclicos/síntese química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Éteres/química , Receptores de Glutamato Metabotrópico/química , Administração Oral , Sítio Alostérico , Animais , Compostos Azabicíclicos/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos/efeitos dos fármacos , Modelos Químicos , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.
Assuntos
Ácidos Dicarboxílicos/síntese química , Ácidos Dicarboxílicos/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Receptores de AMPA/metabolismo , Animais , Cálcio/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Ácidos Dicarboxílicos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirazóis/farmacologia , Ratos , Receptores de AMPA/efeitos dos fármacos , EstereoisomerismoRESUMO
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.
Assuntos
Isoindóis/farmacologia , Lactamas/farmacologia , Oxazóis/farmacologia , Receptor Muscarínico M1/agonistas , Convulsões/induzido quimicamente , Regulação Alostérica , Anfetamina/farmacologia , Animais , Ataxia/induzido quimicamente , Diarreia/induzido quimicamente , Cães , Donepezila , Desenho de Fármacos , Feminino , Humanos , Indanos/farmacologia , Isoindóis/administração & dosagem , Isoindóis/síntese química , Isoindóis/toxicidade , Lactamas/administração & dosagem , Lactamas/síntese química , Lactamas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Oxazóis/administração & dosagem , Oxazóis/síntese química , Oxazóis/toxicidade , Piperidinas/farmacologia , Ratos Wistar , Receptor Muscarínico M1/antagonistas & inibidores , Escopolamina/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Tiadiazóis/farmacologia , Vômito/induzido quimicamenteRESUMO
As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores de Fosfodiesterase/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Córtex Cerebral/metabolismo , Cromatografia Líquida , Descoberta de Drogas , Macaca fascicularis , Ensaio Radioligante , Relação Estrutura-Atividade , Espectrometria de Massas em TandemRESUMO
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Feminino , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Piridinas/efeitos adversos , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Assuntos
Descoberta de Drogas , Ácidos Picolínicos/farmacologia , Receptor Muscarínico M1/agonistas , Tiazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/química , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Receptores de AMPA/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Animais , Sítios de Ligação , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Estabilidade de Medicamentos , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Conformação Proteica , Ratos Sprague-Dawley , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade , Sulfonamidas/química , Tiofenos/química , Adulto JovemRESUMO
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Assuntos
Pirazinas/síntese química , Pirazóis/síntese química , Receptor de Glutamato Metabotrópico 5/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Regulação Alostérica , Animais , Antiparkinsonianos/efeitos adversos , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cães , Discinesia Induzida por Medicamentos/tratamento farmacológico , Células HEK293 , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Levodopa/efeitos adversos , Macaca fascicularis , Células Madin Darby de Rim Canino , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Pirazinas/farmacologia , Pirazinas/toxicidade , Pirazóis/farmacologia , Pirazóis/toxicidade , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.
Assuntos
Descoberta de Drogas , Isoxazóis/química , Isoxazóis/farmacologia , Receptores de AMPA/metabolismo , Absorção , Regulação Alostérica/efeitos dos fármacos , Animais , Ensaios de Triagem em Larga Escala , Humanos , Isoxazóis/metabolismo , Isoxazóis/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Estrutura Terciária de Proteína , Ratos , Receptores de AMPA/química , Relação Estrutura-AtividadeRESUMO
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.