RESUMO
Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.
RESUMO
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Compostos de Anilina/química , Triazóis/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/síntese química , Compostos de Anilina/metabolismo , Animais , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Camundongos , Camundongos Transgênicos , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismoRESUMO
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
Assuntos
Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Desenho de Fármacos , Piperidinas/farmacologia , Triazóis/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Cães , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/química , Piperidinas/metabolismo , Triazóis/química , Triazóis/metabolismoRESUMO
The synthesis and preclinical characterization of two novel, brain penetrating P2X7 compounds will be described. Both compounds are shown to be high potency P2X7 antagonists in human, rat, and mouse cell lines and both were shown to have high brain concentrations and robust receptor occupancy in rat. Compound 7 is of particular interest as a probe compound for the preclinical assessment of P2X7 blockade in animal models of neuro-inflammation.
