RESUMO
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
Assuntos
Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
Assuntos
Benzodiazepinas/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Benzodiazepinas/síntese química , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Macaca fascicularis , Masculino , Camundongos , Microssomos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
GPR84 is an orphan G-protein coupled receptor, expressed on monocytes, macrophages and neutrophils and is significantly upregulated by inflammatory stimuli. The physiological role of GPR84 remains largely unknown. Medium chain fatty acids (MCFA) activate the receptor and have been proposed to be its endogenous ligands, although the high concentrations of MCFAs required for receptor activation generally exceed normal physiological levels. We identified the natural product embelin as a highly potent and selective surrogate GPR84 agonist (originally disclosed in patent application WO2007027661A2, 2007) and synthesized close structural analogs with widely varying receptor activities. These tools were used to perform a comprehensive study of GPR84 signaling and function in recombinant cells and in primary human macrophages and neutrophils. Activation of recombinant GPR84 by embelin in HEK293 cells results in Gi/o as well as G12/13-Rho signaling. In human macrophages, GPR84 initiates PTX sensitive Erk1/2 and Akt phosphorylation, PI-3 kinase activation, calcium flux, and release of prostaglandin E2. In addition, GPR84 signaling in macrophages elicits Gi Gßγ-mediated augmentation of intracellular cAMP, rather than the decrease expected from Giα engagement. GPR84 activation drives human neutrophil chemotaxis and primes them for amplification of oxidative burst induced by FMLP and C5A. Loss of GPR84 is associated with attenuated LPS-induced release of proinflammatory mediators IL-6, KC-GROα, VEGF, MIP-2 and NGAL from peritoneal exudates. While initiating numerous proinflammatory activities in macrophages and neutrophils, GPR84 also possesses GPR109A-like antiatherosclerotic properties in macrophages. Macrophage receptor activation leads to upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. These data suggest that GPR84 may be a target of therapeutic value and that distinct modes of receptor modulation (inhibition vs. stimulation) may be required for inflammatory and atherosclerotic indications.
Assuntos
Benzoquinonas/química , Benzoquinonas/farmacologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Receptores de Superfície Celular/agonistas , Animais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Células HEK293 , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
Assuntos
Aminas/farmacologia , Quinolinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Administração Oral , Aminas/administração & dosagem , Aminas/química , Animais , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Quinolinas/administração & dosagem , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT2 de Serotonina/química , Relação Estrutura-AtividadeRESUMO
The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.
Assuntos
Descoberta de Drogas , Hipertensão Pulmonar/tratamento farmacológico , Receptores de Prostaglandina/agonistas , Animais , Humanos , Hipertensão Pulmonar/induzido quimicamente , Monocrotalina , Agregação Plaquetária/efeitos dos fármacos , Ratos , Receptores de Prostaglandina/metabolismoRESUMO
The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.
Assuntos
Cicloexanos/química , Cicloexanos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Glicemia/análise , Cicloexanos/administração & dosagem , Cicloexanos/farmacocinética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Masculino , Camundongos , Ratos Sprague-Dawley , Ratos Zucker , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
Assuntos
Analgésicos não Narcóticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamação/tratamento farmacológico , Microssomos Hepáticos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Pirazóis/farmacologia , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/química , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Inflamação/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Osteoartrite/metabolismo , Dor/metabolismo , Pirazóis/administração & dosagem , Pirazóis/química , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The G-protein-coupled receptors GPR81, GPR109A, and GPR109B share significant sequence homology and form a small group of receptors, each of which is encoded by clustered genes. In recent years, endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acid metabolites, and we therefore have proposed that this receptor family be named hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA(2) receptor (GPR109A) is a receptor for the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is activated by the ß-oxidation intermediate 3-hydroxy-octanoic acid. HCA(1) and HCA(2) receptors are found in most mammalian species, whereas the HCA(3) receptor is present only in higher primates. The three receptors have in common that they are expressed in adipocytes and are coupled to G(i)-type G-proteins mediating antilipolytic effects in fat cells. HCA(2) and HCA(3) receptors are also expressed in a variety of immune cells. HCA(2) is a receptor for the antidyslipidemic drug nicotinic acid (niacin) and related compounds, and there is an increasing number of synthetic ligands mainly targeted at HCA(2) and HCA(3) receptors. The aim of this article is to give an overview on the discovery and pharmacological characterization of HCAs, and to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature. We will also discuss open questions regarding this receptor family as well as their physiological role and therapeutic potential.
Assuntos
Receptores Acoplados a Proteínas G/classificação , Receptores Nicotínicos/classificação , Terminologia como Assunto , Animais , Clonagem Molecular , Humanos , Agências Internacionais , Modelos Moleculares , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismoRESUMO
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Animais , Humanos , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.
Assuntos
Descoberta de Drogas , Hipoglicemiantes/química , Piperidinas/química , Piperidinas/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Hipoglicemiantes/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Ratos Sprague-DawleyRESUMO
The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.
Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores Histamínicos/química , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Histamínicos H3/química , Sulfonas/química , Animais , Área Sob a Curva , Encéfalo/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica/métodos , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Pirrolidinas/antagonistas & inibidores , Ratos , Sono/efeitos dos fármacos , Temperatura , Vigília/efeitos dos fármacosRESUMO
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
Assuntos
Glicemia/efeitos dos fármacos , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Modelos Animais de Doenças , Glucose/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Oxidiazóis/química , Oxidiazóis/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos ZuckerRESUMO
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
Assuntos
Pirazóis/química , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/química , Vasodilatadores/química , Animais , Cães , Haplorrinos , Humanos , Camundongos , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Tetrazóis/síntese química , Tetrazóis/farmacocinética , Vasodilatadores/síntese química , Vasodilatadores/farmacocinéticaRESUMO
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.
Assuntos
Ácidos Carboxílicos/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Aterosclerose/tratamento farmacológico , Células CHO , Ácidos Carboxílicos/farmacologia , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Humanos , Ligantes , Lipoproteínas HDL/química , Lipoproteínas LDL/química , Modelos Químicos , Niacina/química , Pirazóis/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores NicotínicosRESUMO
A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
Assuntos
Fármacos Antiobesidade/química , Cicloexilaminas/química , Pirimidinas/química , Quinazolinas/química , Receptores de Somatostatina/antagonistas & inibidores , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Ingestão de Alimentos , Humanos , Masculino , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Redução de PesoRESUMO
Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.
Assuntos
Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Ureia/análogos & derivados , Ureia/farmacologia , Humanos , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.
Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Aminas/síntese química , Aminas/farmacologia , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Alcaloides/química , Aminas/química , Animais , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Cinética , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Receptores Histamínicos H3/metabolismo , Relação Estrutura-AtividadeRESUMO
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Assuntos
Alcaloides/farmacocinética , Química Farmacêutica/métodos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/química , Animais , Ligação Competitiva/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos/química , Cinética , Modelos Químicos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Angiotensin (1-7) has been reported to be a ligand for the GPCR MAS1. Small molecule MAS1 modulators have also been recently characterized. Aside from convincing evidence for MAS1 activation of Gq signaling, little is known about MAS1 mediated signaling pathways initiated by these ligands, especially Ang (1-7). We performed a comprehensive characterization of recombinant MAS1 signaling induced by Ang (1-7) and small molecule ligands through numerous G protein-dependent and independent pathways, and in a signaling pathway agnostic approach. We find that small molecule ligands modulate numerous G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, GTPγS binding, ß-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic readout of cellular responses, small molecule agonists produced robust responses. In contrast, Ang (1-7) failed to induce or block signaling in any of these assay platforms. We detected specific binding of radiolabeled Ang (1-7) to rat aortic endothelial cell (RAEC) membranes, but not to recombinant MAS1. Biphasic, concentration-dependent biased signaling responses to Ang II were detected in RAEC. These phases were associated with vastly different DMR characteristics and this likely provides a molecular basis for previously observed concentration-dependent divergent physiological actions of Ang II. Both phases of Ang II signaling in RAECs were potently inhibited by Ang (1-7), providing a plausible molecular mechanism for Ang (1-7) as counter regulator of the Ang II- AT1 axis, responsible at least in part for Ang (1-7) physiological activities.
Assuntos
Angiotensina I/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Angiotensina II/metabolismo , Animais , Arrestinas/metabolismo , Células CHO , Linhagem Celular , Cricetulus , Células Endoteliais/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/fisiologia , Proto-Oncogene Mas , Ratos , beta-Arrestinas/metabolismoRESUMO
Pancreatic beta-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic beta-cell mass. These effects are mediated via stimulation of cAMP through beta-cell GLP-1 receptors. We report that the Galpha(s)-coupled receptor GPR119 is largely restricted to insulin-producing beta-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/A(y) mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.