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1.
Alzheimers Dement ; 20(7): 4540-4558, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38884283

RESUMO

INTRODUCTION: Intraneuronal inclusions composed of tau protein are found in Alzheimer's disease (AD) and other tauopathies. Tau normally binds microtubules (MTs), and its disengagement from MTs and misfolding in AD is thought to result in MT abnormalities. We previously identified triazolopyrimidine-containing MT-stabilizing compounds that provided benefit in AD mouse models and herein describe the characterization and efficacy testing of an optimized candidate, CNDR-51997. METHODS: CNDR-51997 underwent pharmacokinetic, pharmacodynamic, safety pharmacology, and mouse tolerability testing. In addition, the compound was examined for efficacy in 5XFAD amyloid beta (Aß) plaque mice and PS19 tauopathy mice. RESULTS: CNDR-51997 significantly reduced Aß plaques in 5XFAD mice and tau pathology in PS19 mice, with the latter also showing attenuated axonal dystrophy and gliosis. CNDR-51997 was well tolerated at doses that exceeded efficacy doses, with a good safety pharmacology profile. DISCUSSION: CNDR-51997 may be a candidate for advancement as a potential therapeutic agent for AD and/or other tauopathies. Highlights There is evidence of microtubule alterations (MT) in Alzheimer's disease (AD) brain and in mouse models of AD pathology. Intermittent dosing with an optimized, brain-penetrant MT-stabilizing small-molecule, CNDR-51997, reduced both Aß plaque and tau inclusion pathology in established mouse models of AD. CNDR-51997 attenuated axonal dystrophy and gliosis in a tauopathy mouse model, with a strong trend toward reduced hippocampal neuron loss. CNDR-51997 is well tolerated in mice at doses that are meaningfully greater than required for efficacy in AD mouse models, and the compound has a good safety pharmacology profile.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Camundongos Transgênicos , Microtúbulos , Placa Amiloide , Proteínas tau , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Camundongos , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Proteínas tau/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/patologia , Humanos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Peptídeos beta-Amiloides/metabolismo
2.
J Med Chem ; 66(1): 435-459, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36534051

RESUMO

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Pirimidinas/química , Microtúbulos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Tubulina (Proteína)/metabolismo , Relação Estrutura-Atividade
3.
Behav Brain Res ; 415: 113449, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34252501

RESUMO

Many individuals diagnosed with neuropsychiatric disorders, such as autism, attention-deficit/hyperactivity disorder, schizophrenia, and social anxiety disorder, all share a common dimension of aberrant social behavior. Epidemiological data indicate that adverse environmental factors contribute to the risk for neurodevelopmental disorders, including those associated with aberrant social behavior. Early-life exposure to infectious pathogens is one of those adverse environmental factors, suggesting that activation of the immune system during early development may contribute to disease pathology associated with altered social behavior. In the current project, we examined the impact of neonatal infection, with or without juvenile immune activation, on the expression of juvenile social behavior and on the expression of inflammatory cytokines and microglial signaling molecules in the juvenile rat brain. The outcomes of these experiments revealed that neonatal infection significantly decreased juvenile social interaction, but significantly increased juvenile play behavior in male and female rats. Moreover, neonatal infection alone, juvenile immune activation alone, and neonatal infection plus juvenile immune activation all significantly impaired social recognition in juvenile male rats. Juvenile female rats (including controls) did not demonstrate social recognition as measured in our three-chamber social recognition test. Taken together, the behavioral and molecular data presented here support the sensitivity of the developing brain to immune activation, particularly in the expression of age-appropriate social behaviors. These data warrant the design of additional studies to examine the mechanistic relationship between early-life immune activation and aberrant social behavior to develop novel as well as modify existing therapeutic targets and preventative measures to help those who display aberrant social behavior.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/imunologia , Citocinas/imunologia , Microglia/imunologia , Doenças Neuroinflamatórias/imunologia , Comportamento Social , Cognição Social , Fatores Etários , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Infecções por Escherichia coli/complicações , Infecções por Escherichia coli/imunologia , Feminino , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
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