RESUMO
Gamma-secretase modulators (GSMs) selectively lower amyloid-ß42 (Aß42) and are therefore potential disease-modifying drugs for Alzheimer's disease (AD). Here, we report the discovery of imidazopyridine derivatives as GSMs with oral activity on not only Aß42 levels but also cognitive function. Structural optimization of the biphenyl group and pyridine-2-amide moiety of compound 1a greatly improved GSM activity and rat microsomal stability, respectively. 5-{8-[(3,4'-Difluoro[1,1'-biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-methylpyridine-2-carboxamide (1o) showed high in vitro potency and brain exposure, induced a robust reduction in brain Aß42 levels, and exhibited undetectable inhibition of cytochrome p450 enzymes. Moreover, compound 1o showed excellent efficacy against cognitive deficits in AD model mice. These findings suggest that compound 1o is a promising candidate for AD therapeutics.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Imidazóis/farmacologia , Piridinas/farmacologia , Administração Oral , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Disfunção Cognitiva/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Masculino , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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
Metabolic programs are rewired in cancer cells to support survival and tumor growth. Among these, recent studies have demonstrated that glutamate-oxaloacetate transaminase 1 (GOT1) plays key roles in maintaining redox homeostasis and proliferation of pancreatic ductal adenocarcinomas (PDA). This suggests that small molecule inhibitors of GOT1 could have utility for the treatment of PDA. However, the development of GOT1 inhibitors has been challenging, and no compound has yet demonstrated selectivity for GOT1-dependent cell metabolism or selective growth inhibition of PDA cell lines. In contrast, potent inhibitors that covalently bind to the transaminase cofactor pyridoxal-5'-phosphate (PLP), within the active site of the enzyme, have been reported for kynurenine aminotransferase (KAT) and gamma-aminobutyric acid aminotransferase (GABA-AT). Given the drug discovery successes with these transaminases, we aimed to identify PLP-dependent suicide substrate-type GOT1 inhibitors. Here, we demonstrate that PF-04859989, a known KAT2 inhibitor, has PLP-dependent inhibitory activity against GOT1 and shows selective growth inhibition of PDA cell lines.
Assuntos
Aspartato Aminotransferase Citoplasmática/antagonistas & inibidores , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/farmacologia , Aspartato Aminotransferase Citoplasmática/metabolismo , Carcinoma Ductal Pancreático/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , Neoplasias Pancreáticas/enzimologiaRESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Imidazóis/farmacologia , Piridinas/farmacologia , Administração Oral , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Animais , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/química , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/biossíntese , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-AtividadeRESUMO
γ-Secretase is the enzyme responsible for the intramembranous proteolysis of various substrates, such as amyloid precursor protein (APP) and Notch. Amyloid-ß peptide 42 (Aß42) is produced through the sequential proteolytic cleavage of APP by ß- and γ-secretase and causes the synaptic dysfunction associated with memory impairment in Alzheimer's disease. Here, we identified a novel cyclohexylamine-derived γ-secretase modulator, {(1R*,2S*,3R*)-3-[(cyclohexylmethyl)(3,3-dimethylbutyl)amino]-2-[4-(trifluoromethyl)phenyl]cyclohexyl}acetic acid (AS2715348), that may inhibit this pathological response. AS2715348 was seen to reduce both cell-free and cellular production of Aß42 without increasing levels of APP ß-carboxyl terminal fragment or inhibiting Notch signaling. Additionally, the compound increased Aß38 production, suggesting a shift of the cleavage site in APP. The inhibitory potency of AS2715348 on endogenous Aß42 production was similar across human, mouse, and rat cells. Oral administration with AS2715348 at 1 mg/kg and greater significantly reduced brain Aß42 levels in rats, and no Notch-related toxicity was observed after 28-day treatment at 100 mg/kg. Further, AS2715348 significantly ameliorated cognitive deficits in APP-transgenic Tg2576 mice. Finally, AS2715348 significantly reduced brain Aß42 levels in cynomolgus monkeys. These findings collectively show the promise for AS2715348 as a potential disease-modifying drug for Alzheimer's disease.