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1.
Bioorg Med Chem ; 28(22): 115734, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007551

RESUMO

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aß42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aß42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aß42 levels in the plasma of J20 mice, in addition to reducing Aß42 levels in the plasma and brain of Tg2576 mice.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
2.
Bioorg Med Chem Lett ; 26(16): 3928-37, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27426299

RESUMO

The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aß42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Desenho de Fármacos , Tiazóis/química , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Meia-Vida , Humanos , Cinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
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