RESUMEN
AIMS: Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. METHODS: We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. RESULTS: Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. CONCLUSION: The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
RESUMEN
Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/uso terapéutico , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Indoles/química , Indoles/uso terapéutico , Regulación Alostérica/efectos de los fármacos , Animales , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Activadores de Enzimas/farmacocinética , Activadores de Enzimas/farmacología , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Indoles/farmacocinética , Indoles/farmacología , Insulina/sangre , Insulina/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/farmacología , Glucoquinasa/metabolismo , Hipoglucemiantes/farmacología , Piridinas/farmacología , Animales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Descubrimiento de Drogas , Activadores de Enzimas/química , Activadores de Enzimas/farmacocinética , Activadores de Enzimas/uso terapéutico , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Piridinas/química , Piridinas/farmacocinética , Piridinas/uso terapéuticoRESUMEN
GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study. These studies provide strong evidence that reduction of glucose excursion through treatment with 20e is GPR142-mediated, and GPR142 agonists could be used as a potential treatment for type 2 diabetes.
RESUMEN
Aberrant regulation of glucose production makes a critical contribution to the impaired glycemic control that is observed in type 2 diabetes. Although isotopic tracer methods have proven to be informative in quantifying the magnitude of such alterations, it is presumed that one must rely on venous access to administer glucose tracers which therein presents obstacles for the routine application of tracer methods in rodent models. Since intraperitoneal injections are readily used to deliver glucose challenges and/or dose potential therapeutics, we hypothesized that this route could also be used to administer a glucose tracer. The ability to then reliably estimate glucose flux would require attention toward setting a schedule for collecting samples and choosing a distribution volume. For example, glucose production can be calculated by multiplying the fractional turnover rate by the pool size. We have taken a step-wise approach to examine the potential of using an intraperitoneal tracer administration in rat and mouse models. First, we compared the kinetics of [U-13C]glucose following either an intravenous or an intraperitoneal injection. Second, we tested whether the intraperitoneal method could detect a pharmacological manipulation of glucose production. Finally, we contrasted a potential application of the intraperitoneal method against the glucose-insulin clamp. We conclude that it is possible to 1) quantify glucose production using an intraperitoneal injection of tracer and 2) derive a "glucose production index" by coupling estimates of basal glucose production with measurements of fasting insulin concentration; this yields a proxy for clamp-derived assessments of insulin sensitivity of endogenous production.
Asunto(s)
Glucemia/metabolismo , Indicadores y Reactivos , Animales , Glucemia/efectos de los fármacos , Isótopos de Carbono , Dieta Alta en Grasa , Femenino , Técnica de Clampeo de la Glucosa , Hipoglucemiantes/farmacología , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Resistencia a la Insulina , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Proyectos Piloto , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Rosiglitazona , Tiazolidinedionas/farmacologíaRESUMEN
MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.
Asunto(s)
Carbolinas/química , Carbolinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Carbolinas/síntesis química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The imidazolyl-tetrahydro-ß-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (17e, MK-1421).
RESUMEN
Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-à-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.
RESUMEN
A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents.
RESUMEN
Glucagon-like peptide-1 (GLP-1) and oxyntomodulin (OXM) are peptide hormones secreted postprandially from the gut that stimulate insulin secretion in a glucose-dependent manner. OXM activates both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). It has been suggested that OXM acutely modulates glucose metabolism solely through GLP1R agonism. Because OXM activates the GLP1R with lower affinity than GLP-1, we generated a peptide analog (QâE, OXMQ3E) that does not exhibit glucagon receptor agonist activity but retains the same affinity as OXM for GLP1R. We compared the effects of OXM and OXMQ3E in a glucose tolerance test and, to better characterize the effect on glucose metabolism, we performed controlled infusions of OXM or OXMQ3E during a hyperglycemic clamp performed in wild-type, Glp1r(-/-), and Gcgr(-/-) mice. Our findings show that OXM, but not OXMQ3E, activates the GCGR in vivo. Second, OXM and OXMQ3E improve glucose tolerance following an acute glucose challenge and during a hyperglycemic clamp in mice. Finally, OXM infusion during a glucose clamp reduces the glucose infusion rate (GIR) despite a simultaneous increase in insulin levels in Glp1r(-/-) mice, whereas OXM and OXMQ3E increase GIR to a similar extent in Gcgr(-/-) mice. In conclusion, activation of the GCGR seems to partially attenuate the acute beneficial effects on glucose and contributes to the insulinotropic action of oxyntomodulin.
Asunto(s)
Péptido 1 Similar al Glucagón/farmacología , Glucosa/metabolismo , Oxintomodulina/farmacología , Animales , Glucemia/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Glucagón/genética , Receptores de Glucagón/metabolismoRESUMEN
This letter provides the first pharmacological proof of principle that the sst3 receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-ß-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-ß-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic ß-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst3 knockout mice. Thus, we have shown that antagonism of sst3 represents a new mechanism with potential in treating type 2 diabetes mellitus.
RESUMEN
A structure-activity relationship study of the imidazolyl-ß-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.
RESUMEN
In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.
Asunto(s)
Modelos Animales de Enfermedad , Dislipidemias/sangre , Lípidos/sangre , Animales , Cricetinae , Perros , Dislipidemias/tratamiento farmacológico , Ácidos Grasos/sangre , Humanos , Ratones , Primates , Simvastatina/uso terapéutico , Triglicéridos/sangreRESUMEN
The design, synthesis, and structure-activity relationship (SAR) for a series of ß-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.
Asunto(s)
Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Propionatos/síntesis química , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Ciclización , Modelos Animales de Enfermedad , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Propionatos/química , Propionatos/farmacocinéticaRESUMEN
Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
Asunto(s)
Descubrimiento de Drogas/métodos , Receptores Acoplados a Proteínas G/agonistas , Tiazolidinedionas/química , Animales , Ratones , Ratones Noqueados , Unión Proteica/fisiología , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad , Tiazolidinedionas/agonistas , Tiazolidinedionas/farmacologíaRESUMEN
Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated with high fat diet and a low dose of streptozotocin to induce insulin resistance and impaired insulin secretion, respectively. Diabetic mice were treated with sitagliptin or the sulfonylurea agent glipizide as admixture to high fat diet for ten weeks. Sustained reduction of blood glucose, HbA(1c), circulating glucagon and improvement in oral glucose tolerance were observed in mice treated with sitagliptin. In contrast, glipizide improved glycemic control only during the early weeks and to a lesser degree compared to sitagliptin, and had no effect on circulating glucagon levels or glucose tolerance. The improvement in glycemic control in sitagliptin-treated mice was associated with a significant increase in glucose-dependent insulin secretion in both perfused pancreas and isolated islets. Importantly, in contrast to the lack of effect by glipizide, sitagliptin significantly restored beta and alpha cell mass as well as alpha/beta cell ratio. These data indicate that DPP-4 inhibition by sitagliptin provided better overall improvement of glycemic control compared to glipizide in the high fat diet/streptozotocin induced diabetic mouse model. The ability of sitagliptin to enhance islet cell function may offer insight into the potential for disease modification.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Glipizida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Pirazinas/uso terapéutico , Triazoles/uso terapéutico , Animales , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Grasas de la Dieta/administración & dosificación , Dipeptidil Peptidasa 4 , Glipizida/metabolismo , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Hemoglobina Glucada/análisis , Hipoglucemiantes/metabolismo , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Antígeno Ki-67/metabolismo , Lípidos/sangre , Hígado/química , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos , Pirazinas/metabolismo , Fosfato de Sitagliptina , Triazoles/metabolismo , Triglicéridos/análisisRESUMEN
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Imidazoles/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Cristalografía por Rayos X/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Diseño de Fármacos , Péptido 1 Similar al Glucagón/química , Humanos , Hidrólisis , Imidazoles/farmacología , Concentración 50 Inhibidora , Macaca mulatta , Ratones , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Fosfato de Sitagliptina , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
The presence of serum in biological samples often negatively impacts the quality of in vitro assays. However, assays tolerant of serum are useful for assessing the in vivo availability of a small molecule for its target. Electrophysiology assays of ion channels are notoriously sensitive to serum because of their reliance on the interaction of the plasma membrane with a recording electrode. Here we investigate the tolerance of an automated electrophysiology assay for a voltage-gated potassium (K(V)) channel to serum and purified plasma proteins. The delayed rectifier channel, K(V)2.1, stably expressed in Chinese hamster ovary cells produces large, stable currents on the IonWorks Quattro platform (MDS Analytical Technologies, Sunnyvale, CA), making it an ideal test case. K(V)2.1 currents recorded on this platform are highly resistant to serum, allowing recordings in as high as 33% serum. Using a set of compounds related to the K(V) channel blocker, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone, we show that shifts in compound potency with whole serum or isolated serum proteins can be reliably measured with this assay. Importantly, this assay is also relatively insensitive to plasma, allowing the creation of a bioassay for inhibitors of K(V)2.1 channel activity. Here we show that such a bioassay can quantify the levels of the gating modifier, guangxitoxin-1E, in plasma samples from mice dosed with the peptide. This study demonstrates the utility of using an automated electrophysiology platform for measuring serum shifts and for bioassays of ion channel modulators.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Canales de Potasio de Tipo Rectificador Tardío/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Bloqueadores de los Canales de Potasio/farmacología , Animales , Autoanálisis , Células CHO , Cricetinae , Cricetulus , Interpretación Estadística de Datos , Diálisis , Electrofisiología , Humanos , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiología , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Unión ProteicaRESUMEN
OBJECTIVE: Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40. RESEARCH DESIGN AND METHODS: We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)). RESULTS: Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically. CONCLUSIONS: GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
Asunto(s)
Glucemia/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Animales , Animales Recién Nacidos , Células CHO , Línea Celular , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/farmacología , Ácidos Grasos no Esterificados/farmacología , Femenino , Humanos , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/sangre , Obesidad/etiología , Obesidad/metabolismo , Embarazo , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologíaRESUMEN
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.