RESUMO
AIMS/HYPOTHESIS: Antagonism of the glucagon receptor (GCGR) represents a potential approach for treating diabetes. Cpd-A, a potent and selective GCGR antagonist (GRA) was studied in preclinical models to assess its effects on alpha cells. METHODS: Studies were conducted with Cpd-A to examine the effects on glucose-lowering efficacy, its effects in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor, and the extent and reversibility of alpha cell hypertrophy associated with GCGR antagonism in mouse models. RESULTS: Chronic treatment with Cpd-A resulted in effective and sustained glucose lowering in mouse models in which endogenous murine Gcgr was replaced with human GCGR (hGCGR). Treatment with Cpd-A also led to stable, moderate elevations in both glucagon and glucagon-like peptide 1 (GLP-1) levels, which were completely reversible and not associated with a hyperglycaemic overshoot following termination of treatment. When combined with a DPP-4 inhibitor, Cpd-A led to additional improvement of glycaemic control correlated with elevated active GLP-1 levels after glucose challenge. In contrast to Gcgr-knockout mice in which alpha cell hypertrophy was detected, chronic treatment with Cpd-A in obese hGCGR mice did not result in gross morphological changes in pancreatic tissue. CONCLUSIONS/INTERPRETATION: A GRA lowered glucose effectively in diabetic models without significant alpha cell hypertrophy during or following chronic treatment. Treatment with a GRA may represent an effective approach for glycaemic control in patients with type 2 diabetes, which could be further enhanced when combined with DPP-4 inhibitors.
Assuntos
Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/sangue , Células Secretoras de Glucagon/patologia , Glucagon/sangue , Obesidade/sangue , Obesidade/patologia , Receptores de Glucagon/antagonistas & inibidores , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Gorduras na Dieta/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipertrofia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Receptores de Glucagon/deficiência , Receptores de Glucagon/genética , Estreptozocina/efeitos adversosRESUMO
Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.
Assuntos
Agonistas Adrenérgicos beta/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Sulfonamidas/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Lipólise/efeitos dos fármacos , Macaca mulatta , Masculino , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 3RESUMO
A study of 4-acylaminobenzenesulfonamides in a cloned human beta 3 adrenergic receptor assay resulted in the discovery of n-hexylurea, L-755,507 (22). This 0.43 nM beta 3 agonist, which is > 440-fold selective over both beta 1 and beta 2 binding, is among the most potent human beta 3 agonists reported to date.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Receptores Adrenérgicos beta/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Desenho de Fármacos , Humanos , Conformação Molecular , Estrutura Molecular , Receptores Adrenérgicos beta/fisiologia , Receptores Adrenérgicos beta 1/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 3 , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Pyridineethanolamine derivatives containing cyanoguanidine or nitroethylenediamine moieties were examined as human beta3 adrenergic receptor (AR) agonists. Notably, indoline derivatives 6a and 11 were potent beta3 AR agonists (beta3 EC50 = 13 and 19 nM, respectively), which showed good selectivity over binding to and minimal activation of the beta1 and beta2 ARs.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Adenilil Ciclases/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Membrana Celular/química , Técnicas de Química Combinatória , Cricetinae , Diaminas/química , Etano/análogos & derivados , Etano/química , Guanidinas/química , Humanos , Concentração Inibidora 50 , Nitroparafinas/química , Ensaio Radioligante , Receptores Adrenérgicos beta/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-AtividadeRESUMO
Tetrahydroisoquinoline derivatives containing a 4-(hexylureido)benzenesulfonamide were examined as human beta3 adrenergic receptor (AR) agonists. Notably, 4,4-biphenyl derivative 9 was a 6 nM full agonist of the beta3 AR. Naphthyloxy compound 18 (beta3 EC50 = 78 nM) did not activate the beta1 and beta2 ARs at 10 microM, and showed >1000-fold selectivity over binding to the beta1 and beta2 ARs.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/síntese química , Amidas/síntese química , Isoquinolinas/síntese química , Peptídeos/síntese química , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Amidas/química , Desenho de Fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Modelos Moleculares , Conformação Molecular , Peptídeos/química , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3 , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Cães , Relação Dose-Resposta a Droga , Humanos , Infusões Parenterais , Isoproterenol/farmacologia , Lipólise/efeitos dos fármacos , Macaca mulatta , Ligação Proteica , Receptores Adrenérgicos beta 3/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Taquicardia/induzido quimicamente , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética , BenzenossulfonamidasRESUMO
Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Receptores Adrenérgicos beta/metabolismo , Administração Oral , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Cães , Frequência Cardíaca/efeitos dos fármacos , Humanos , Macaca mulatta , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta 3 , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacocinética , Ureia/farmacologiaRESUMO
The cyclopentylpropylimidazolidinone L-766,892 is a potent beta3 AR agonist (EC50 5.7 nM, 64% activation) with 420- and 130-fold selectivity over binding to the beta1 and beta2 ARs, respectively. In anesthetized rhesus monkeys, L-766,892 elicited dose-dependent hyperglycerolemia (ED50 0.1 mg/kg) with minimal effects on heart rate.
Assuntos
Agonistas Adrenérgicos beta/síntese química , Ciclopentanos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos beta/metabolismo , Agonistas de Receptores Adrenérgicos beta 1 , Agonistas de Receptores Adrenérgicos beta 2 , Agonistas Adrenérgicos beta/farmacocinética , Agonistas Adrenérgicos beta/farmacologia , Animais , Células CHO , Cricetinae , Ciclopentanos/farmacocinética , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Macaca mulatta , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta 3 , Relação Estrutura-AtividadeRESUMO
Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.