RESUMO
P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been investigated and disclosed in patent applications or primary literature since 2015. While a crystal structure of the receptor to aid in the design of novel chemical structures remains elusive, many of the chemotypes that have been disclosed contain similarities, with an amide motif present in all series that have been explored to date. Several of the recent antagonists described are brain penetrant, and two compounds are currently in clinical trials for CNS indications. Additionally, brain penetrant PET ligands have been developed that aid in measuring target engagement and these ligands can potentially be used as biomarkers.
Assuntos
Transtornos do Humor/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Humanos , Ligantes , Estrutura Molecular , Transtornos do Humor/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Antagonistas do Receptor Purinérgico P2X/químicaRESUMO
The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists.
Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X7/metabolismo , Animais , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/metabolismo , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Meia-Vida , Humanos , Inflamação/prevenção & controle , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7/químicaRESUMO
The synthesis, SAR, and preclinical characterization of a series of substituted 6,7-dihydro[1,2,4]triazolo[4,3]pyrazin-8(5H)-one P2X7 receptor antagonists are described. Optimized leads from this series comprise some of the most potent human P2X7R antagonists reported to date (IC50s<1nM). They also exhibit sufficient potency and oral bioavailability in rat to enable extensive in vivo profiling. Although many of the disclosed compounds are peripherally restricted, compound 11d is brain penetrant and upon oral administration demonstrated dose-dependent target engagement in rat hippocampus as determined by ex vivo receptor occupancy with radiotracer 5 (ED50=0.8mg/kg).
Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirazinas/farmacologia , Triazóis/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/farmacocinética , Hipocampo/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Receptores Purinérgicos P2X7/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacocinética , TrítioRESUMO
The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
Assuntos
Antagonistas do Receptor Purinérgico P2X/química , Pirazinas/química , Receptores Purinérgicos P2X7/química , Triazóis/química , Animais , Meia-Vida , Humanos , Microssomos/metabolismo , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1ß. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pKi 9.1 ± 0.07) and human (pKi 7.9 ± 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium)]-induced release of IL-1ß in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1ß induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the α-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.
Assuntos
Fármacos do Sistema Nervoso Central/metabolismo , Fármacos do Sistema Nervoso Central/farmacologia , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Piperazinas/metabolismo , Piperazinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Animais , Animais Recém-Nascidos , Fármacos do Sistema Nervoso Central/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/uso terapêutico , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Piperazinas/uso terapêutico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
The use of P2X7 antagonists to treat inflammatory disorders has garnered considerable interest in recent years. An increasing number of literature reports support the role of P2X7 in inflammatory pathways of the peripheral and central nervous systems (CNSs). A number of CNS indications such as neuropsychiatric and neurodegenerative disorders and neuropathic pain have been linked to a neuroinflammatory response, and clinical studies have shown that inflammatory biomarkers can be mitigated by modulating P2X7. Recent scientific and patent literature describing novel P2X7 antagonists has indicated their use in CNS disorders. In addition, several reports have disclosed the results of administering P2X7 antagonists in pre-clinical models of CNS disease or investigating brain uptake. This review describes small molecule P2X7 antagonists that have first appeared in the literature since 2009 and have potential therapeutic utility in the CNS, or for which new data have emerged implicating their use in CNS indications.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.
Assuntos
Encéfalo , Pirimidinas , Receptores de N-Metil-D-Aspartato , Animais , Ratos , Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
Assuntos
Azepinas/síntese química , Boroidretos/química , Antagonistas dos Receptores Histamínicos H3/síntese química , Hidroxiprolina/química , Pirrolidinas/síntese química , Sódio/química , Azepinas/química , Cromatografia/métodos , Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores Histamínicos H3/química , Espectroscopia de Ressonância Magnética/métodos , Pirrolidinas/química , Solubilidade , Solventes/química , Estereoisomerismo , TemperaturaRESUMO
The structure based drug design, synthesis and structure-activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.
Assuntos
Benzamidas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Triazóis/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Químicos , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
Assuntos
Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Indóis/síntese química , Indóis/farmacologia , Tiofenos/síntese química , Tiofenos/farmacologia , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Indicadores e Reagentes , Indóis/farmacocinética , Isomerismo , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Tiofenos/farmacocinéticaRESUMO
The pre-clinical characterization of novel aryloxypyridine amides that are histamine H(3) receptor antagonists is described. These compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination as development candidates.
Assuntos
Azepinas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Piridinas/farmacologia , Amidas/química , Animais , Azepinas/química , Avaliação Pré-Clínica de Medicamentos , Piridinas/química , RatosRESUMO
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
Assuntos
Azepinas/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3/química , Administração Oral , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Encéfalo/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Camundongos , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.
Assuntos
Antipsicóticos/síntese química , Desenho de Fármacos , Imidazóis/química , Piridinas/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Encéfalo/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/patologia , Nanoestruturas/química , Permeabilidade/efeitos dos fármacos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Solubilidade , Relação Estrutura-AtividadeRESUMO
Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1H-pyrrolo[3,2-b]pyridine core. Lead optimization efforts included increasing brain penetration as well as decreasing cytochrome P450 inhibition and hERG channel binding. The series was also optimized to reduce metabolic turnover in human and rat. Compounds 9, 25, 30, and 34 have good in vitro GluN2B potency and good predicted absorption, but moderate to high projected clearance. They were assessed in vivo to determine their target engagement. All four compounds achieved >75% receptor occupancy after an oral dose of 10 mg/kg in rat. Compound 9 receptor occupancy was measured in a dose-response experiment, and its ED50 was found to be 2.0 mg/kg.
RESUMO
Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.
Assuntos
Isoquinolinas/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Pirróis/farmacologia , Animais , Área Sob a Curva , Autorradiografia , Barreira Hematoencefálica/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Elevação dos Membros Posteriores , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Atividade Motora/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacocinética , Pirróis/química , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , EstereoisomerismoRESUMO
The synthesis and biological activity of a new series of 2-aryloxymethylmorpholine histamine H(3) antagonists is described. The new compounds are high affinity histamine H(3) ligands that penetrate the CNS and occupy the histamine H(3) receptor in rat brain.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Morfolinas/farmacologia , Animais , Encéfalo/metabolismo , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Morfolinas/síntese química , Morfolinas/farmacocinética , RatosRESUMO
The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
Assuntos
Azepinas/síntese química , Antagonistas dos Receptores Histamínicos H3/síntese química , Piperazinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Azepinas/farmacocinética , Azepinas/farmacologia , Encéfalo/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
Assuntos
Inibidores da Colinesterase/química , Antagonistas dos Receptores Histamínicos H3/química , Modelos Moleculares , Doença de Alzheimer/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Relação Quantitativa Estrutura-AtividadeRESUMO
Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1ß release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1ß release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1ß release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1ß release and microglial activation leading to efficacy in two models of anhedonia in rodents.
Assuntos
Anedonia/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Mediadores da Inflamação/metabolismo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Receptores Purinérgicos P2X7/fisiologia , Anedonia/fisiologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.