RESUMEN
BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.
Asunto(s)
Cálculos Biliares/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Piridinas/administración & dosificación , Solventes/administración & dosificación , Administración Tópica , Animales , Células CHO , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos/métodos , Embrión no Mamífero , Femenino , Cálculos Biliares/patología , Fármacos Gastrointestinales/efectos adversos , Humanos , Mesocricetus , Ratones , Ratones Endogámicos ICR , Células 3T3 NIH , Piridinas/efectos adversos , Solventes/efectos adversos , Células Vero , Pez CebraRESUMEN
A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49â¯nM and 18â¯nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 &32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.
Asunto(s)
Receptores Acoplados a Proteínas G/agonistas , Tiazoles/farmacología , Animales , Línea Celular , Chlorocebus aethiops , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.
Asunto(s)
Amidas/farmacología , Diseño de Fármacos , Receptores Acoplados a Proteínas G/agonistas , Amidas/síntesis química , Amidas/química , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/administración & dosificación , Prueba de Tolerancia a la Glucosa , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citología , Intestinos/efectos de los fármacos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The refractive index is the fundamental property of all optical materials and dictates Snell's law, propagation speed, wavelength, diffraction, energy density, absorption and emission of light in materials. Experimentally realized broadband refractive indices remain <40, even with intricately designed artificial media. Herein, we demonstrate a measured index >1,800 resulting from a mesoscopic crystal with a dielectric constant greater than three million. This gigantic enhancement effect originates from the space-filling curve concept from mathematics. The principle is inherently very broad band, the enhancement being nearly constant from zero up to the frequency of interest. This broadband giant-refractive-index medium promises not only enhanced resolution in imaging and raised fundamental absorption limits in solar energy devices, but also compact, power-efficient components for optical communication and increased performance in many other applications.
RESUMEN
A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Glucemia/análisis , Glucemia/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Secreción de Insulina , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Conformación Molecular , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential as treatment for osteoporosis as well as metabolic syndrome including type 2 diabetes mellitus. Here, we investigated the anti-diabetic, anti-adipogenic, and anti-osteoporotic activity of KR-67500, as a novel selective 11ß-HSD1 inhibitor. Cellular 11ß-HSD1 activity was tested based on a homogeneous time-resolved fluorescence method. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) levels were measured in diet-induced obese (DIO)-C57BL/6 mice administered KR-67500 (50â mg/kg per day, p.o.) for 28 days and, additionally, its anti-diabetic effect was evaluated by OGTT and ITT. The in vitro anti-adipogenic effect of KR-67500 was determined by Oil Red O Staining. The in vitro anti-osteoporotic activity of KR-67500 was evaluated using bone morphogenetic protein 2 (BMP2)-induced osteoblast differentiation and receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model systems. KR-67500 improved the in vivo glucose tolerance and insulin sensitivity in DIO-C57BL/6 mice. KR-67500 suppressed cortisone-induced differentiation of 3T3-L1 cells into adipocytes. KR-67500 enhanced BMP2-induced osteoblastogenesis in C2C12 cells and inhibited RANKL-induced osteoclastogenesis in mouse bone marrow-derived macrophages. KR-67500, a new selective 11ß-HSD1 inhibitor, may provide a new therapeutic window in the prevention and/or treatment of type 2 diabetes, obesity, and/or osteoporosis.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Obesidad/tratamiento farmacológico , Osteoblastos/patología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Células 3T3-L1 , Adipogénesis/efectos de los fármacos , Animales , Células de la Médula Ósea/patología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/genética , Dieta , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/patología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
It has been reported that the selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11ß-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11ß-HSD1 activity in human and mouse 11ß-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11ß-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11ß-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11ß-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11ß-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Antiinflamatorios/farmacología , Dieta/efectos adversos , Hipoglucemiantes/farmacología , Obesidad/tratamiento farmacológico , Tiazolidinas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéutico , Cortisona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/metabolismo , Hipoglucemiantes/uso terapéutico , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiopatología , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Obesos , Modelos Moleculares , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/fisiopatología , Conformación Proteica , Tiazolidinas/metabolismo , Tiazolidinas/uso terapéuticoRESUMEN
Glucocorticoid excess (Cushing's syndrome) causes metabolic syndrome such as visceral obesity, insulin resistance, diabetes mellitus, dyslipidaemia and hypertension. The selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 4-(2-(1,1-dioxido-6-(2,4,6-trichlorophenyl)-1,2,6-thiadiazinan-2-yl)acetamido)adamantane-1-carboxamide (KR-67183), a novel selective 11ß-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and diet-induced obese (DIO) mice. KR-67183 concentration-dependently inhibited 11ß-HSD1 activity in human and mouse 11ß-HSD1 over-expressed cells and in the ex vivo assay of C57BL/6 mice. In the study with DIO mice, the administration of KR-67183 (20 and 50mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity with suppressed 11ß-HSD1 activity in the liver and fat. However, KR-67183 showed no change in the adrenal gland weight/body weight ratio and plasma corticosterone concentration in DIO mice. Further, KR-67183 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, PPARγ2 and GLUT4, and 11ß-HSD1 activity. Taken together, it is suggested that a selective 11ß-HSD1 inhibitor, KR-67183, may provide a new therapeutic window in the prevention and treatment without toxicity in type 2 diabetes with obesity.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adipogénesis/efectos de los fármacos , Dieta/efectos adversos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Obesidad/patología , Tiadiazinas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Células 3T3-L1 , Adamantano/metabolismo , Adamantano/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/fisiopatología , Animales , Biomarcadores/metabolismo , Células CHO , Cricetinae , Cricetulus , Inhibidores Enzimáticos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Resistencia a la Insulina , Ratones , Simulación del Acoplamiento Molecular , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Conformación Proteica , Tiadiazinas/metabolismoRESUMEN
A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11ß-HSD1. Among this series, 18e showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.
RESUMEN
A series of ß-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Tiazolidinas/síntesis química , Administración Oral , Animales , Cristalografía por Rayos X , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Modelos Animales de Enfermedad , Perros , Activación Enzimática/efectos de los fármacos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Tiazolidinas/química , Tiazolidinas/farmacologíaRESUMEN
The selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential for treating type 2 diabetes mellitus and metabolic syndrome. In the present study, we investigated the anti-diabetic and anti-adipogenic effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), as a 11ß-HSD1 inhibitor; we also investigated the underlying molecular mechanisms in the cortisone-induced 3T3-L1 adipogenesis model system and C57BL/6-Lep(ob/ob) mice. KR-66344 concentration-dependently inhibited 11ß-HSD1 activity in human liver microsome, mouse C2C12 myotube and human SW982 cells. In the C57BL/6-Lep(ob/ob) mice study, the administration of KR-66344 (200mg/kg/d, orally for 5 days) improved the glucose intolerance as determined by the oral glucose tolerance test, in which the area under the curve (AUC) of the plasma glucose concentration was significantly reduced by 27% compared with the vehicle treated group. Further, KR-66344 suppressed adipocyte differentiation on cortisone-induced adipogenesis in 3T3-L1 cells is associated with the suppression of the cortisone-induced mRNA levels of FABP4, G3PD, PPARγ2 and Glut4, and 11ß-HSD1 expression and activity. Our results additionally demonstrate evidence showing that KR-66344 improved glycemic control and inhibited adipogenesis via 11ß-HSD1 enzyme activity. Taken together, these results may provide evidence of the therapeutic potential of KR-66344, as a 11ß-HSD1 inhibitor, in obesity and type 2 diabetes patients with metabolic syndrome.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adipogénesis/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Óxidos S-Cíclicos/farmacología , Hipoglucemiantes/farmacología , Tiazinas/farmacología , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/enzimología , Adipocitos/metabolismo , Animales , Fármacos Antiobesidad/uso terapéutico , Cortisona/farmacología , Óxidos S-Cíclicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/uso terapéutico , Leptina/genética , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/enzimología , Obesidad/metabolismo , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiazinas/uso terapéuticoRESUMEN
In the continuation of our 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor research, cyclic sulfonamide derivatives with an acetamide group at the 2-position were synthesized and evaluated for their abilities to inhibit 11ß-HSD1. Among this series, Compound 34 showed good in vitro activity toward human 11ß-HSD1, selectivity against 11ß-HSD2, microsomal stability, good pharmacokinetic and safety profiles human ether-a-go-go related gene (hERG and cytochrome P450 (CYP)). Also, a docking study explained the activity difference between human and mouse 11ß-HSD1.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Acetamidas/química , Inhibidores Enzimáticos/química , Sulfonamidas/química , Tiazinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Animales , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , RatonesRESUMEN
A new series of thiazolidine derivatives with an adamantyl group was synthesized and evaluated for their ability to inhibit 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1). Our initial compound 5a showed a weak inhibitory activity. Significant improvements in potency were achieved by substituent modification. The potent compound 8g (E) showed good in vitro inhibitory activity toward human 11ß-HSD1, selectivity toward 11ß-HSD2, metabolic stability, pharmacokinetic, and safety profile. Furthermore, this compound significantly inhibited 11ß-HSD1 activity in rat and monkey models, and showed improved glycemic control in KKAy mice.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/química , Inhibidores Enzimáticos/síntesis química , Tiazolidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Adamantano/síntesis química , Adamantano/farmacocinética , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-Actividad , Tiazolidinas/síntesis química , Tiazolidinas/farmacocinéticaRESUMEN
A new series of cyclic sulfonamide derivatives was synthesized and evaluated for their ability to inhibit 11beta-HSD1. Cyclic sulfonamides with phenylacetyl substituents at the 2-position showed nanomolar inhibitory activities. Among them, compound 4e exhibited a good in vitro inhibitory activity and selectivity toward human 11beta-HSD2.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Sulfonamidas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Animales , Línea Celular , Humanos , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , Sulfonamidas/metabolismo , Sulfonamidas/farmacologíaRESUMEN
A new synthetic small molecule, compound 1, which induced a neuronal differentiation from mesenchymal stem cells (MSCs) with an excellent efficiency, was identified. Furthermore the differentiated cell by 1 showed the neural electrophysiological and cholinergic neuron properties.
Asunto(s)
Células Madre Mesenquimatosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Fenómenos Electrofisiológicos , Perfilación de la Expresión Génica , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/fisiología , Neuronas/citología , Neuronas/fisiología , RatasRESUMEN
Compounds with homopiperazine skeleton are designed to find a potent DPP-IV inhibitor without inhibiting CYP. Thus a series of beta-aminoacyl-containing homopiperazine derivatives was synthesized and evaluated. Compounds with acid moiety were found to be potent inhibitors of DPP-IV without inhibiting CYP 3A4. More specifically, compound 7m showed nanomolar activity with no inhibition towards five subtypes of CYPs, was considered as a prototype for further derivatization. Based on its X-ray co-crystal structure with human DPP-IV, we identified compounds 7s and 7t which showed good in vitro activity, no CYP inhibition, and good selectivity.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Piperazinas/química , Sitios de Unión , Cristalografía por Rayos X/métodos , Citocromo P-450 CYP3A/química , Diabetes Mellitus/tratamiento farmacológico , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Piperazina , Pirazinas/farmacología , Fosfato de Sitagliptina , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
A series of pyrazoline derivatives with beta-amino acyl group were synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV. Several pyrazoline derivatives exhibited submicromolar inhibitory activities against DPP-IV. X-ray co-crystal structure of initial hit compound 1h was determined. Among this series, carboxylic acid substituted pyrazoline derivative 2u was the most active and greatly decreased the inhibitory activity toward CYP3A4 enzyme.
Asunto(s)
Aminas/química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Inhibidores de la Dipeptidil-Peptidasa IV/química , Humanos , Concentración 50 Inhibidora , Pirazoles/química , Relación Estructura-ActividadRESUMEN
A series of novel indene N-oxide derivatives were prepared by various synthetic methods and evaluated for their ability to activate PPARgamma. The best PPARgamma agonist in this series was 9h, which showed an EC(50) value of 15 nM.
Asunto(s)
Indenos/química , Indenos/farmacología , PPAR gamma/agonistas , Relación Estructura-ActividadRESUMEN
Inhibitors of dipeptidyl peptidase IV (DPP-IV) have been shown to be effective treatments for type 2 diabetes. A series of beta-aminoacyl-containing cyclic hydrazine derivatives were synthesized and evaluated as DPP-IV inhibitors. One member of this series, (R)-3-amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (10f), showed potent in vitro activity, good selectivity and in vivo efficacy in mouse models. Also, the binding mode of compound 10f was determined by X-ray crystallography.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hidrazinas/síntesis química , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Péptido 1 Similar al Glucagón/metabolismo , Hidrazinas/farmacología , Concentración 50 Inhibidora , Cinética , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Conformación Molecular , Estructura Terciaria de ProteínaRESUMEN
Agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) are of interest as a treatment for diabetes, which prompted the identification of a new class of non-TZD PPAR gamma agonist. Moreover, compound 14c has displayed the most active agonistic activity with an EC50 value of 50 nM, in addition to exhibiting a new binding mode in the X-ray cocrystal structure.