RESUMEN
A mild condition via PPh3/I2/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.
RESUMEN
GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism.
Asunto(s)
Tejido Adiposo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Lipólisis , Receptores Acoplados a Proteínas G/metabolismo , Tejido Adiposo/efectos de los fármacos , Animales , Células CHO , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/patología , Regulación de la Expresión Génica/efectos de los fármacos , Resistencia a la Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/fisiopatología , Lipólisis/efectos de los fármacos , Masculino , Ratones , Ratas , Receptores Acoplados a Proteínas G/agonistasRESUMEN
The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
Asunto(s)
Carboxipeptidasas/antagonistas & inhibidores , Ciclohexanos/química , Ciclohexanos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Animales , Ciclohexanos/farmacocinética , Descubrimiento de Drogas , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Obesidad/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2.
Asunto(s)
Biocatálisis , Glutatión Transferasa/metabolismo , Piridinas/farmacocinética , Compuestos de Azufre/farmacocinética , Animales , Bilis/química , Biotransformación/fisiología , Cromatografía Liquida , Citosol/metabolismo , Perros , Glutatión/metabolismo , Haplorrinos , Humanos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Masculino , Microsomas Hepáticos/enzimología , Estructura Molecular , NADP/metabolismo , Piridinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Especificidad de la Especie , Compuestos de Azufre/metabolismo , Espectrometría de Masas en TándemRESUMEN
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Diseño de Fármacos , Furanos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Benzopiranos , Perros , Furanos/química , Furanos/farmacología , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Noqueados , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Relación Estructura-ActividadRESUMEN
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Asunto(s)
Naftiridinas/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Administración Oral , Animales , Ingestión de Alimentos , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Farmacocinética , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Obesidad/tratamiento farmacológico , Pirimidinas/química , Administración Oral , Animales , Cannabinoides/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Estructura Terciaria de Proteína , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Relación Estructura-ActividadRESUMEN
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.
RESUMEN
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.
Asunto(s)
Anemia/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Piridazinas/farmacología , Pirimidinas/farmacología , Administración Oral , Anemia/enzimología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Piridazinas/administración & dosificación , Piridazinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Piranos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Unión Competitiva , Peso Corporal/efectos de los fármacos , Línea Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Perros , Agonismo Inverso de Drogas , Ingestión de Alimentos/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Glucurónidos/metabolismo , Haplorrinos , Hepatocitos/metabolismo , Humanos , Ratones , Ratones Noqueados , Modelos Moleculares , Conformación Molecular , Piranos/farmacocinética , Piranos/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Conducta Alimentaria/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temperatura , Tolueno/químicaRESUMEN
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Receptor Cannabinoide CB1/antagonistas & inhibidores , Administración Oral , Animales , Sitios de Unión , Ratones , Ratones Noqueados , Modelos Químicos , Naftiridinas/síntesis química , Receptor Cannabinoide CB1/agonistasRESUMEN
Structure-activity relationship studies for two series of 2-benzyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyridines having either a 3-cyano or 3-carboxamide moiety resulted in the preparation of the 2-(3,4-difluorobenzyloxy)-3-nitrile analog 10d and the 2-(3,4-difluorobenzyloxy)-3-(N-propylcarboxamide) analog 16c, (hCB1 IC(50)=1.3 and 1.7 nM, respectively) as potent and selective hCB1 inverse agonists. Their synthesis and biological activities are described herein.