RESUMEN

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions.

Asunto(s)

Imidazoles/efectos adversos , Linagliptina/farmacología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pirazinas/efectos adversos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Glucemia/metabolismo , Familia 2 del Citocromo P450/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Imidazoles/farmacología , Insulina/sangre , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Perilipina-2/metabolismo , Pirazinas/farmacología , Esteroide Hidroxilasas/metabolismo , Triglicéridos/sangre

RESUMEN

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.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Imidazoles/farmacología , Piridinas/farmacología , Administración Oral , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular Tumoral , Disfunción Cognitiva/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Masculino , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Aspartato Aminotransferasa Citoplasmática/antagonistas & inhibidores , Carcinoma Ductal Pancreático/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/farmacología , Aspartato Aminotransferasa Citoplasmática/metabolismo , Carcinoma Ductal Pancreático/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Neoplasias Pancreáticas/enzimología

RESUMEN

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 µM in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aß42 levels in mice.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Administración Oral , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Masculino , Ratones , Ratones Endogámicos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Relación Estructura-Actividad

RESUMEN

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 (IC50 = 7.1 µM) 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 (IC50 = 0.39 µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.

Asunto(s)

Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Descubrimiento de Drogas , Compuestos Heterocíclicos/farmacología , Imidazoles/farmacología , Piridinas/farmacología , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Animales , Línea Celular Tumoral , Citocromo P-450 CYP3A/metabolismo , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/biosíntesis , Piridinas/administración & dosificación , Piridinas/química , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Acetatos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Encéfalo/efectos de los fármacos , Ciclohexilaminas/farmacología , Fármacos Neuroprotectores/farmacología , Acetatos/efectos adversos , Acetatos/farmacocinética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Cognición/efectos de los fármacos , Ciclohexilaminas/efectos adversos , Ciclohexilaminas/farmacocinética , Modelos Animales de Enfermedad , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Transgénicos , Estructura Molecular , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Nootrópicos/efectos adversos , Nootrópicos/química , Nootrópicos/farmacología , Fragmentos de Péptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Notch/metabolismo

RESUMEN

Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.

Asunto(s)

Antiinflamatorios/síntesis química , Quinazolinas/farmacocinética , Receptores CCR4/antagonistas & inhibidores , Administración Oral , Aminas , Animales , Antiinflamatorios/farmacocinética , Quimiotaxis/efectos de los fármacos , Dermatitis/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Ratones , Piperidinas , Quinazolinas/farmacología , Relación Estructura-Actividad

RESUMEN

A general and mild catalytic allylation of carbonyl compounds, applicable to aldehydes, ketones, and imines is developed using allyltrimethoxysilane as the allylating reagent. The reaction proceeds smoothly with 1-10 mol % of CuCl and TBAT in THF at ambient temperature. Mechanism studies indicated that the copper alkoxide, allylfluorodimethoxysilane, and allyltrimethoxysilane are essential to promote the reaction efficiently. Preliminary extension of the reaction to the first catalytic enantioselective allylation of ketones using an allylsilane produced the product with 61% ee from acetophenone, using a CuCl-p-tol-BINAP-TBAT catalyst (15 mol %).