RESUMO
Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.
Assuntos
Esclerose Múltipla , Oligodendroglia , Receptor Muscarínico M1 , Remielinização , Animais , Humanos , Camundongos , Ratos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Antagonistas Muscarínicos/farmacologia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M1/antagonistas & inibidores , Remielinização/efeitos dos fármacosRESUMO
Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.
Assuntos
Esclerose Múltipla , Receptores de Ácidos Lisofosfatídicos , Remielinização , Animais , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Remielinização/efeitos dos fármacos , Humanos , Camundongos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacosRESUMO
Compound 21 (AM432) was identified as a potent and selective antagonist of the DP(2) receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP(2) receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing.
Assuntos
Fenilacetatos/química , Piridinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Cães , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Humanos , Inflamação/tratamento farmacológico , Camundongos , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapêutico , Piridinas/farmacocinética , Piridinas/uso terapêutico , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismoRESUMO
Nitric-oxide synthases (NOS) generate nitric oxide (NO) through the oxidation of l-arginine. Inappropriate or excessive production of NO by NOS is associated with the pathophysiology of various disease states. Efforts to treat these disorders by developing arginine mimetic, substrate-competitive NOS inhibitors as drugs have met with little success. Small-molecule-mediated inhibition of NOS dimerization represents an intriguing alternative to substrate-competitive inhibition. An ultra-high-throughput cell-based screen of 880,000 small molecules identified a novel quinolinone with inducible NOS (iNOS) inhibitory activity. Exploratory chemistry based on this initial screening hit resulted in the synthesis of KLYP956, which inhibits iNOS at low nanomolar concentrations. The iNOS inhibitory potency of KLYP956 is insensitive to changes in concentrations of the substrate arginine, or the cofactor tetrahydrobiopterin. Mechanistic analysis suggests that KLYP956 binds the oxygenase domain in the vicinity of the active site heme and inhibits iNOS and neuronal NOS (nNOS) by preventing the formation of enzymatically active dimers. Oral administration of KLYP956 [N-(3-chlorophenyl)-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide] inhibits iNOS activity in a murine model of endotoxemia and blocks pain behaviors in a formalin model of nociception. KLYP956 thus represents the first nonimidazole-based inhibitor of iNOS and nNOS dimerization and provides a novel pharmaceutical alternative to previously described substrate competitive inhibitors.
Assuntos
Inibidores Enzimáticos/farmacologia , Fluoroquinolonas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Tiazóis/farmacologia , Administração Oral , Animais , Células Cultivadas , Dimerização , Humanos , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo I/química , Óxido Nítrico Sintase Tipo II/química , Dor/tratamento farmacológico , Especificidade da EspécieRESUMO
The lysophosphatidic acid receptor type 1 (LPA1) is 1 of 6 known receptors of the extracellular signaling molecule lysophosphatidic acid. It mediates effects such as cell proliferation, migration, and differentiation. In the lung, LPA1 is involved in pathways leading, after lung tissue injury, to pulmonary fibrosis instead of normal healing, by mediating fibroblast recruitment and vascular leakage. Thus, a LPA1 PET radiotracer may be useful for studying lung fibrosis or for developing LPA1-targeting drugs. We developed and evaluated the radiotracer 11C-BMT-136088 (1-(4'-(3-methyl-4-(((1(R)-(3-11C-methylphenyl)ethoxy)carbonyl)amino)isoxazol-5-yl)-[1,1'-biphenyl]-4-yl)cyclopropane-1-carboxylic acid) in rhesus monkeys to image LPA1 in the lung in vivo with PET. Methods: The study consisted of 3 parts: test-retest scans; self-saturation to estimate the tracer's in vivo dissociation constant, nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND); and dosimetry. In the first 2 parts, the radiotracer was administered using a bolus-plus-infusion protocol, the arterial input function was measured, and the animals underwent 2 scans per day separated by about 4 h. Lung regions of interest were segmented, and the tissue density estimated, from CT images. A fixed blood volume correction was applied. The tracer volume of distribution (VT) was estimated using multilinear analysis 1 (MA1) or equilibrium analysis (EA). Results:11C-BMT-136088 baseline VT was 1.83 ± 0.16 (MA1, n = 5) or 2.1 ± 0.55 (EA, n = 7) mL of plasma per gram of tissue in the left and right lung regions of interest, with a test-retest variability of -6% (MA1, n = 1) or -1% ± 14% (EA, n = 2). For the self-saturation study, 11C-BMT-136088 VND and BPND were estimated to be 0.9 ± 0.08 mL of plasma per gram of tissue and 1.1 ± 0.14, respectively. The unlabeled drug dose and plasma concentration leading to a 50% reduction of 11C-BMT-136088 specific binding were 73 ± 30 nmol/kg and 28 ± 12 nM, respectively. The average plasma free fraction was 0.2%; thus, the tracer's in vivo dissociation constant was estimated to be 55 pM. For the dosimetry study, the highest organ dose was in the liver (43.1 ± 4.9 and 68.9 ± 9.4 µSv/MBq in reference human male and female phantoms, respectively), and the effective dose equivalent was 6.9 ± 0.6 and 8.7 ± 0.6 µSv/MBq, respectively. Conclusion: Specific binding of 11C-BMT-136088 can be reliably measured to quantify LPA1 in the lungs of rhesus monkeys in vivo.
Assuntos
Radioisótopos de Carbono/metabolismo , Ácidos Carboxílicos/metabolismo , Pulmão/diagnóstico por imagem , Receptores de Ácidos Lisofosfatídicos/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Feminino , Processamento de Imagem Assistida por Computador , Cinética , Ligantes , Pulmão/metabolismo , Macaca mulatta , Masculino , Tomografia por Emissão de Pósitrons , Radioquímica , Radiometria , Distribuição TecidualRESUMO
2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.
Assuntos
Ansiolíticos/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Ansiolíticos/química , Ansiolíticos/farmacologia , Ansiedade/psicologia , Encéfalo/metabolismo , Cálcio/metabolismo , Linhagem Celular , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Humanos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
Assuntos
Ansiolíticos/síntese química , Ansiolíticos/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/química , Estrutura Molecular , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
In vivo receptor occupancy of mGlu5 receptor antagonists was quantified in rat and mouse brain using the mGlu5 receptor selective antagonist [3H]3-methoxy-5-(pyridin-2-ylethynyl)pyridine) ([3H]methoxy-PEPy). Administration of [3H]methoxy-PEPy (50 microCi/kg i.v.) to mGlu5 receptor-deficient mice revealed binding at background levels in forebrain, whereas wild-type mice exhibited 14-fold higher binding in forebrain relative to cerebellum. Systemic administration of the mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) reduced the binding of [3H]methoxy-PEPy in rats and mice, reflecting mGlu5 receptor occupancy by these compounds. MPEP (10 mg/kg i.p.) and MTEP (3 mg/kg i.p.) maintained >75% receptor occupancy for 2 h in rats, while in mice MPEP and MTEP achieved >75% occupancy for only 30 and 15 min, respectively. Compound levels in plasma were substantially lower in mice suggesting species differences in receptor occupancy result from differences in absorption or metabolism of the compounds. These findings demonstrate that [3H]methoxy-PEPy is useful for determining the occupancy of mGlu5 receptors in the brain.
Assuntos
Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Sítios de Ligação , Hipocampo/metabolismo , Injeções Intraperitoneais , Injeções Intravenosas , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Prosencéfalo/metabolismo , Piridinas/metabolismo , Ensaio Radioligante/métodos , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , Especificidade da Espécie , Tiazóis/metabolismo , Tiazóis/farmacologia , Fatores de Tempo , TrítioRESUMO
The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Antiasmáticos/síntese química , Indóis/síntese química , Ácidos Pentanoicos/síntese química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Administração Oral , Animais , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Lavagem Broncoalveolar , Inibidores das Enzimas do Citocromo P-450 , Cães , Feminino , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
We evaluated the in vivo pharmacological properties of AM803 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, a selective five-lipoxygenase-activating protein (FLAP) inhibitor, using rat and mouse models of acute inflammation. Oral administration of AM803 (1 mg/kg) resulted in sustained inhibition of ex vivo ionophore-challenged whole blood LTB4 biosynthesis with >90% inhibition for up to 12 h and an EC50 of approximately 7 nM. When rat lungs were challenged in vivo with calcium-ionophore, AM803 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50s of 0.12 mg/kg and 0.37 mg/kg, respectively. The inhibition measured 16 h following a single oral dose of 3 mg/kg was 86% and 41% for LTB4 and CysLTs, respectively. In an acute inflammation setting, AM803 dose-dependently reduced LTB4, CysLTs, plasma protein extravasation and neutrophil influx induced by peritoneal zymosan injection. Finally, AM803 increased survival time in mice exposed to a lethal intravenous injection of platelet activating factor (PAF). The magnitude of effect was similar to that of an inhibitor of five-lipoxygenase (5-LO) and LTA4 hydrolase but superior to a leukotriene CysLT1 receptor antagonist. In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Indóis/farmacologia , Inflamação/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Ácidos Pentanoicos/farmacologia , Propionatos/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase , Animais , Doença Crônica , Cisteína/biossíntese , Modelos Animais de Doenças , Feminino , Humanos , Indóis/farmacocinética , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Leucotrieno B4/biossíntese , Leucotrienos/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/uso terapêutico , Fator de Ativação de Plaquetas/farmacologia , Propionatos/farmacocinética , Propionatos/uso terapêutico , Ratos , Especificidade por Substrato , Zimosan/farmacologiaRESUMO
There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42--potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.
Assuntos
Descoberta de Drogas , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Dor/tratamento farmacológico , Multimerização Proteica/efeitos dos fármacos , Pirazinas/administração & dosagem , Pirazinas/farmacologia , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Administração Oral , Animais , Linhagem Celular , Constrição Patológica/induzido quimicamente , Constrição Patológica/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fluoroquinolonas/química , Fluoroquinolonas/uso terapêutico , Formaldeído/toxicidade , Humanos , Concentração Inibidora 50 , Lipopolissacarídeos/toxicidade , Camundongos , Óxido Nítrico Sintase Tipo II/química , Óxido Nítrico Sintase Tipo II/metabolismo , Estrutura Quaternária de Proteína , Pirazinas/química , Pirazinas/uso terapêutico , Quinolonas/química , Quinolonas/uso terapêutico , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.
Assuntos
Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tetrazóis/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitatórios/química , Cinética , Camundongos , Estrutura Molecular , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [11C]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed.
Assuntos
Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitatórios/síntese química , Tomografia por Emissão de Pósitrons , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Autorradiografia/métodos , Sítios de Ligação/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Química Encefálica , Mapeamento Encefálico , Radioisótopos de Carbono/farmacocinética , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/classificação , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Radioisótopos de Flúor/farmacocinética , Humanos , Técnicas In Vitro , Macaca mulatta , Imageamento por Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Estatística como Assunto , Fatores de TempoRESUMO
The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.
Assuntos
Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Físico-Química , Humanos , Técnicas In Vitro , Ligantes , Masculino , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5 , Tiazóis/farmacocinéticaRESUMO
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.
Assuntos
Ansiolíticos/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/fisiologia , Tiazóis/síntese química , Animais , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiedade , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Cinética , Modelos Moleculares , Piridinas/química , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
Structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery of 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl)pyridine (10)-a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability.
Assuntos
Ansiolíticos/farmacocinética , Nitrilas/farmacocinética , Piridinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tetrazóis/química , Tetrazóis/farmacocinética , Administração Oral , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/química , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Estrutura Molecular , Nitrilas/química , Piridinas/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.