RESUMO
γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aß42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aß42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Picolinas/farmacologia , Doença de Alzheimer/enzimologia , Amidas/química , Animais , Células HEK293 , Humanos , Picolinas/química , Ratos , Ratos Sprague-DawleyRESUMO
The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.
Assuntos
Isoquinolinas/farmacologia , Isoquinolinas/farmacocinética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Mutantes/antagonistas & inibidores , Mutação , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/síntese química , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ratos , Especificidade por SubstratoRESUMO
A series of 8-anilinoimidazo[4,5-g]quinoline-7-carbonitriles was synthesized and evaluated as Src kinase inhibitors. Several aniline substituents were surveyed, as well as water-solubilizing groups at the C-2 and N-3 positions. Potent Src inhibitors were identified, with N-3 providing the best position for an additional water-solubilizing group.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Nitrilas/síntese química , Nitrilas/farmacologia , Quinolinas/síntese química , Quinolinas/farmacologia , Quinases da Família src/antagonistas & inibidores , Fenômenos Químicos , Físico-Química , Indicadores e Reagentes , Solubilidade , Relação Estrutura-AtividadeRESUMO
A series of substituted 4-anilino-7-phenyl-3-quinolinecarbonitriles has been prepared as Src kinase inhibitors. Optimal activity is observed with compounds that have basic amines attached via the para position of the 7-phenyl ring, and a hydrogen atom at the C-6 position. The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells.
