RESUMO
Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.
RESUMO
Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.
RESUMO
Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.
RESUMO
Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.
Assuntos
Descoberta de Drogas , Proteínas Plasmáticas de Ligação ao Retinol/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Vitamina A/sangueRESUMO
Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
Assuntos
Aminopiridinas/química , Ativadores de Enzimas/química , Glucoquinase/metabolismo , Tiadiazóis/química , Animais , Área Sob a Curva , Glicemia/metabolismo , Catálise , Diabetes Mellitus Experimental/tratamento farmacológico , Glucose/metabolismo , Teste de Tolerância a Glucose , Hepatócitos/metabolismo , Homeostase , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/citologia , Cinética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Fosforilação , Ratos , Ratos Sprague-DawleyRESUMO
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
Assuntos
Descoberta de Drogas , Oxidiazóis/farmacologia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Quinolinas/síntese química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.
Assuntos
Descoberta de Drogas , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/química , Piridinas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Anilina/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Receptores Acoplados a Proteínas G/química , Relação Estrutura-AtividadeRESUMO
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Assuntos
Descoberta de Drogas , Receptores Nucleares Órfãos/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Assuntos
Receptores Nucleares Órfãos/agonistas , Isoformas de Proteínas/agonistas , Pirróis/síntese química , Sítios de Ligação , Células CACO-2 , Cristalografia por Raios X , Genes Reporter , Células HEK293 , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/química , Ligação Proteica , Isoformas de Proteínas/química , Pirróis/farmacologia , Relação Estrutura-Atividade , TransfecçãoRESUMO
The discovery and parallel synthesis of potent, small molecule antagonists of Neuromedin B receptor based on the ary-hexahydro-dibenzodiazepin-1-one core is described.
Assuntos
Benzodiazepinonas/síntese química , Química Farmacêutica/métodos , Receptores da Bombesina/antagonistas & inibidores , Animais , Benzodiazepinonas/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Elétrons , Peptídeo Liberador de Gastrina/química , Células HeLa , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Peptídeos/química , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.
Assuntos
PPAR delta/agonistas , PPAR gama/agonistas , Tiazóis/química , Animais , Simulação por Computador , Cristalografia por Raios X , PPAR delta/metabolismo , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley , Tiazóis/síntese química , Tiazóis/farmacologiaRESUMO
Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin. Analysis of the RBP4-A1120 co-crystal structure reveals that A1120 induces critical conformational changes at the RBP4-transthyretin interface. Administration of A1120 to mice lowers serum RBP4 and retinol levels but, unexpectedly, does not improve insulin sensitivity. In addition, we show that Rpb4(-/-) mice display normal insulin sensitivity and are not protected from high fat diet-induced insulin resistance. We conclude that lowering RBP4 levels does not improve insulin sensitivity in mice. Therefore, RBP4 lowering may not be an effective strategy for treating diabetes.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Piperidinas/química , Proteínas Plasmáticas de Ligação ao Retinol , Vitamina A/sangue , Animais , Cristalografia por Raios X , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Gorduras na Dieta/efeitos adversos , Humanos , Insulina/metabolismo , Resistência à Insulina , Ligantes , Camundongos , Camundongos Knockout , Piperidinas/farmacologia , Estrutura Terciária de Proteína , Proteínas Plasmáticas de Ligação ao Retinol/agonistas , Proteínas Plasmáticas de Ligação ao Retinol/química , Proteínas Plasmáticas de Ligação ao Retinol/metabolismoRESUMO
Retinol binding protein 4 (RBP4) is a serum protein that serves as the major transport protein for retinol (vitamin A). Recent reports suggest that elevated levels of RBP4 are associated with insulin resistance and that insulin sensitivity may be improved by reducing serum RBP4 levels. This can be accomplished by administration of small molecules, such as fenretinide, that compete with retinol for binding to RBP4 and disrupt the protein-protein interaction between RBP4 and transthyretin (TTR), another serum protein that protects RBP4 from renal clearance. We developed a fluorescence resonance energy transfer (FRET) assay that measures the interaction between RBP4 and TTR and can be used to determine the binding affinities of RBP4 ligands. We present an allosteric model that describes the pharmacology of interaction among RBP4, TTR, retinol, and fenretinide, and we show data that support the model. We show that retinol increases the affinity of RBP4 for TTR by a factor of 4 and determine the affinity constants of fenretinide and retinyl acetate. The assay may be useful for characterizing small molecule ligands that bind to RBP4 and disrupt its interaction with TTR. In addition, such a model could be used to describe other protein-protein interactions that are modulated by small molecules.
Assuntos
Fenretinida/metabolismo , Pré-Albumina/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Sítios de Ligação , Diterpenos , Fenretinida/química , Transferência Ressonante de Energia de Fluorescência/métodos , Humanos , Cinética , Ligantes , Modelos Biológicos , Pré-Albumina/química , Proteínas Plasmáticas de Ligação ao Retinol/química , Ésteres de Retinil , Relação Estrutura-Atividade , Vitamina A/análogos & derivados , Vitamina A/química , Vitamina A/metabolismoRESUMO
The objective of this study was to demonstrate the efficacy of a novel peroxisome proliferator-activated receptor (PPAR) agonist and known PPARalpha and PPARdelta agonists to increase HDL-cholesterol (HDL-C) in the St. Kitts vervet, a nonhuman primate model of atherosclerosis. Four groups (n = 6) were studied and each group was assigned one of the following "treatments": a) vehicle only (vehicle); b) the PPARdelta selective agonist GW501516 (GW); c) the PPARalpha/delta agonist T913659 (T659); and d) the PPARalpha agonist TriCor (fenofibrate). No statistically significant changes were seen in body weight, total plasma cholesterol, plasma triglycerides, VLDL-C, LDL-C, or apolipoprotein B (apoB) concentrations. Each of the PPARalpha and PPARdelta agonists investigated in this study increased plasma HDL-C, apoA-I, and apoA-II concentrations and increased HDL particle size in St. Kitts vervets. The maximum percentage increase in HDL-C from baseline for each group was as follows: vehicle, 5%; GW, 43%; T659, 43%; and fenofibrate, 20%. Treatment with GW and T659 resulted in an increase in medium-sized HDL particles, whereas fenofibrate showed increases in large HDL particles. These data provide additional evidence that PPARalpha and PPARdelta agonists (both mixed and selective) have beneficial effects on HDL-C in these experimental primates.
Assuntos
HDL-Colesterol/sangue , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Chlorocebus aethiops , Masculino , Tamanho da Partícula , Tiazóis/farmacologiaRESUMO
The design and parallel synthesis of potent, small molecule partial agonists of Neuromedin B receptor based on the 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide core is described.