RESUMEN
GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.
Asunto(s)
Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Tetrazoles/farmacología , Tiofenos/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/química , Tiofenos/químicaRESUMEN
Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.
Asunto(s)
Hipoglucemiantes/farmacología , Pirazinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/farmacología , Compuestos de Bifenilo/farmacología , Células CHO , Cricetulus , Perros , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucurónidos/biosíntesis , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Macaca fascicularis , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenilpropionatos/farmacología , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/química , Pirazinas/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/farmacologíaRESUMEN
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.
Asunto(s)
Diseño de Fármacos , Imidazoles/química , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/química , Piridinas/química , Animales , Sitios de Unión , Prueba de Tolerancia a la Glucosa , Semivida , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Insulina/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.
Asunto(s)
Amidas/farmacología , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Animales , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described.
Asunto(s)
Analgésicos/química , Analgésicos/uso terapéutico , Bencimidazoles/química , Bencimidazoles/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Canales Catiónicos TRPM/antagonistas & inhibidores , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Frío , Perros , Células HEK293 , Humanos , Ratas , Canales Catiónicos TRPM/metabolismoRESUMEN
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.
Asunto(s)
Amidas/farmacología , Compuestos Heterocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.
RESUMEN
The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Colágeno , Relación Dosis-Respuesta a Droga , Ratones , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Factores de TiempoRESUMEN
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.
Asunto(s)
Antiinflamatorios/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Fenilendiaminas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Simulación por Computador , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Fenilendiaminas/síntesis química , Fenilendiaminas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermoresponsive to cool to cold temperatures (8-28 °C) and also may be activated by chemical agonists such as menthol and icilin. Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia. The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels. Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain. Taken together, the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/síntesis química , Isoxazoles/síntesis química , Canales Catiónicos TRPM/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Disponibilidad Biológica , Constricción Patológica/tratamiento farmacológico , Constricción Patológica/fisiopatología , Perros , Células HEK293 , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Técnicas In Vitro , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Ratas , Relación Estructura-ActividadRESUMEN
A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Imidazoles/síntesis química , Piperidinas/síntesis química , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/etiología , Artritis Experimental/patología , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacología , Conformación Proteica , Ratas , Ratas Endogámicas Lew , Receptor de Factor Estimulante de Colonias de Macrófagos/química , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.
Asunto(s)
Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Imidazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Neoplasias Óseas/enzimología , Neoplasias Óseas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Desnudos , Osteoclastos/efectos de los fármacos , Osteoclastos/patología , Ratas , Ratas Sprague-Dawley , Receptor de Factor Estimulante de Colonias de Macrófagos/sangre , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Especificidad por Sustrato , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
A number of fluorinated 1-aryl-tetrahydrocyclopentapyrazoles were synthesized and their insecticidal activity was evaluated. Some of the fluorinated compounds had significant insecticidal properties.
Asunto(s)
Insectos/efectos de los fármacos , Insecticidas/síntesis química , Insecticidas/toxicidad , Pirazoles/síntesis química , Pirazoles/toxicidad , Animales , Encéfalo/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes , Membrana Celular/metabolismo , Moscas Domésticas/efectos de los fármacos , Moscas Domésticas/crecimiento & desarrollo , Insecticidas/química , Ratones , Estructura Molecular , Neuronas/efectos de los fármacos , Pirazoles/química , Ensayo de Unión Radioligante , Receptores de GABA/metabolismo , Relación Estructura-ActividadRESUMEN
A convenient synthetic route to novel 4-arylpyrazoles is described. The potential for insecticidal activity through GABA channel blockage by this series of compounds, as well as their selectivity for insect versus mammalian receptors, are explored through in vitro and in vivo assays.
Asunto(s)
Insecticidas/síntesis química , Pirazoles/síntesis química , Receptores de GABA/efectos de los fármacos , Animales , Moscas Domésticas , Insecticidas/farmacología , Ratones , Pirazoles/metabolismo , Pirazoles/farmacología , Receptores de GABA/metabolismo , Relación Estructura-ActividadRESUMEN
Pyrazole 2a is a novel, potent ligand for insect GABA receptors obtained from housefly head membrane preparations (K(i)=8 nM). It is 500-fold selective against the mammalian receptor (mouse brain preparations). Its specifically tritiated version (2b) was synthesized by reduction of disulfide 10 with NaBH(4) followed by alkylation with [3H(3)]-CH(3)I.