RESUMO
Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer's disease because they can selectively decrease pathogenic amyloid-ß42 (Aß42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1'-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aß42 levels with an IC50 value of 0.091⯵M in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aß42 levels in mice.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Administração Oral , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-ß 42 (Aß42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aß42 (IC50â¯=â¯7.1⯵M) without changing total production of Aß. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aß42 (IC50â¯=â¯0.39⯵M) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.