RESUMO
Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Inibidores de Fosfoinositídeo-3 Quinase , Humanos , Linfócitos B , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular TumoralRESUMO
PI3Kδ inhibitors have been approved for B-cell malignancies like CLL, small lymphocytic lymphoma, and so forth. However, currently available PI3Kδ inhibitors are nonoptimal, showing weakness against at least one of the several important properties: potency, isoform selectivity, and/or pharmacokinetic profile. To come up with a PI3Kδ inhibitor that overcomes all these deficiencies, a pharmacophoric expansion strategy was employed. Herein, we describe a systematic transformation of a "three-blade propeller" shaped lead, 2,3-disubstituted quinolizinone 11, through a 1,2-disubstituted quinolizinone 20 to a novel "four-blade propeller" shaped 1,2,3-trisubstituted quinolizinone 34. Compound 34 has excellent potency, isoform selectivity, metabolic stability across species, and exhibited a favorable pharmacokinetic profile. Compound 34 also demonstrated a differentiated efficacy profile in human germinal center B and activated B cell-DLBCL cell lines and xenograft models. Compound 34 qualifies for further evaluation as a candidate for monotherapy or in combination with other targeted agents in DLBCLs and other forms of iNHL.
Assuntos
Antineoplásicos/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Quinolizinas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/síntese química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/farmacocinética , Cães , Descoberta de Drogas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Quinolizinas/síntese química , Quinolizinas/metabolismo , Quinolizinas/farmacocinética , Células RAW 264.7 , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-ß and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.
Assuntos
Amidas/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Fumaratos/uso terapêutico , Resistência à Insulina , Amidas/administração & dosagem , Amidas/farmacologia , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fumaratos/administração & dosagem , Fumaratos/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Inflamação/patologia , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Músculos/efeitos dos fármacos , Músculos/metabolismo , Curva ROC , Ratos , Ratos WistarRESUMO
CONTEXT: Tamarindus indica L. (Leguminosae) is widely used as a traditional medicine for the management of diabetes mellitus (DM) in India, in addition to its anti-inflammatory activity. The present study has been designed to understand the correlation involved between antidiabetic and anti-inflammatory action of aqueous seed extract of T. indica (TSE) in diabetic rats. OBJECTIVE: In view of the fact that fatty acid synthesis and insulin release from islets of pancreas are regulated by sterol regulatory element-binding proteins (SREBP-1c) and cytosolic calcium, respectively, the objectives of present study were to determine the influence of TSE on SREBP-1c mRNA and to investigate the intracellular islets calcium [Ca²âº](I) involvement and ß-cell mass preservation in insulin secretagogue action of TSE. MATERIALS AND METHODS: The effect of 4 weeks oral treatment (120 and 240 mg/kg) of high-performance liquid chromatography (HPLC) standardized TSE was studied in streptozotocin (STZ)-induced diabetic male Wistar rats. Reverse transcription-PCR (RT-PCR) and a spectrofluorometer were used for mRNA concentration and islets [Ca²âº](I) determination, respectively. The TUNEL assay was followed to study the pancreatic apoptosis. RESULTS: TSE (120 and 240 mg/kg) showed positive correlation with [Ca²âº](I) and insulin release. The anti-inflammatory action of TSE was significant on nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in addition to a favorable effect on ß-cell neogenesis and improved mRNA concentration of SREBP-1c. DISCUSSION AND CONCLUSION: The results suggest that anti-inflammatory action of Tamarind seeds on ß-cell cells of islets and cytokines contribute toward its antidiabetic activity by way of complex mechanisms of [Ca²âº](I) handling and through SREBP-1c gene in liver.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Fígado/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tamarindus/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Apoptose/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Hipoglicemiantes/administração & dosagem , Índia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Fígado/imunologia , Fígado/metabolismo , Masculino , Óxido Nítrico/metabolismo , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Sementes/química , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Técnicas de Cultura de Tecidos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Inhibitors of dipeptidyl peptidase-4 (DPP-IV), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major question concerns the potential ability of long term DPP-IV inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ß-cell mass due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of vildagliptin (PKF-275-055), on glycemic control, pancreatic ß-cell mass, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. To induce NIDDM, streptozotocin (STZ) 90 mg/kg was administered i.p. to a group of 2 days old pups. Diabetic rats were administered orally with vildagliptin analog PKF-275-055. Saline treated animals served as diabetic control. Significant and dose-dependent correction of postprandial hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with PKF-275-055 showed increased the number of insulin-positive ß-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with PKF-275-055 significantly increased insulin content, glycogen content and total proteins content; and decreased the inflammatory markers i.e. nitric oxide and TNF-alpha. The present studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor having potential to reduce inflammation that might be a potential agent for type 2 diabetes.
Assuntos
Adamantano/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Nitrilas/uso terapêutico , Pirrolidinas/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Glicemia/análise , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/genética , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glicogênio/metabolismo , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Nitratos/metabolismo , Nitrilas/farmacologia , Nitritos/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pirrolidinas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic ß-cell mass and function due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor vildagliptin on glycemic control, pancreatic ß-cell mass and function, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. METHOD: To induce NIDDM, STZ (sigma chemicals, USA) (90 mg/kg) was administered i.p. to a group of 2 days old pups. Another group of pups received only saline. The pups were weaned for 21 days, and 6 weeks after the injection of STZ, the animals were checked for fasting glucose level (FPG) ≥160 mg/dl were considered as diabetic. RESULTS: Significant and dose-dependent correction of postprandial and fasting hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with vildagliptin showed increase in the number of insulin-positive ß-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with vildagliptin significantly increased insulin content; and decreased the nitric oxide and TNF-alpha concentration. CONCLUSION: These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of diabetes mellitus by modifying the courses of the disease.
Assuntos
Adamantano/análogos & derivados , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Adamantano/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Feminino , Homeostase/efeitos dos fármacos , Insulina/sangue , Células Secretoras de Insulina/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Estreptozocina/efeitos adversos , Resultado do Tratamento , VildagliptinaRESUMO
The present study aims to investigate the combined and individual treatment of aliskiren and olmesartan for 8 weeks in streptozotocin induced diabetic rats provide an effective blockade of RAAS by improving glucose homeostasis, glomerular filtration rate along with renal variables thereby delaying the progression of the disease. Streptozotocin induced diabetic rats were administered with aliskiren (10mg/kg/day), olmesartan (6mg/kg/day) alone and in combination. To identify the glucose homeostasis, translocation of glucose transporter proteins in liver and muscle was observed by their expression after treatment. Glomerular filtration rate is estimated using serum creatinine, cystatin C and beta 2 microglobulin. This study also examined the effects of combination and monotherapy on various renal variables viz. albumin, total proteins, TGF-ß, TNF-α, VEGF, nitric oxide, adiponectin and erythropoeitin. In addition, histopathological and anti-apoptotic profile of kidney was also investigated. The present study indicates that dual blockade of RAAS improved glucose homeostasis and confirms the nephroprotective effects of the combined treatment of aliskiren and olmesartan independent of their antihypertensive property in the STZ induced diabetes. In addition, its antifibrotic, antiproteinuric effects indicate that combination treatment might be potential as an important therapeutic option for chronic fibrotic diseases in renal complications.