ABSTRACT
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.
Subject(s)
Blood Glucose/metabolism , Glucagon-Like Peptide 1/blood , Glucagon-Secreting Cells/pathology , Glucagon/blood , Obesity/blood , Obesity/pathology , Receptors, Glucagon/antagonists & inhibitors , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/chemically induced , Dietary Fats/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Hypertrophy , In Vitro Techniques , Male , Mice , Mice, Knockout , Obesity/etiology , Receptors, Glucagon/deficiency , Receptors, Glucagon/genetics , Streptozocin/adverse effectsABSTRACT
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.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adenylyl Cyclases/drug effects , Adenylyl Cyclases/metabolism , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cell Membrane/chemistry , Combinatorial Chemistry Techniques , Cricetinae , Diamines/chemistry , Ethane/analogs & derivatives , Ethane/chemistry , Guanidines/chemistry , Humans , Inhibitory Concentration 50 , Nitroparaffins/chemistry , Radioligand Assay , Receptors, Adrenergic, beta/metabolism , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adrenergic beta-3 Receptor Antagonists , Adrenergic beta-Agonists/chemical synthesis , Amides/chemical synthesis , Isoquinolines/chemical synthesis , Peptides/chemical synthesis , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Amides/chemistry , Drug Design , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Molecular Conformation , Peptides/chemistry , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Adrenergic, beta-3/metabolism , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Dogs , Dose-Response Relationship, Drug , Humans , Infusions, Parenteral , Isoproterenol/pharmacology , Lipolysis/drug effects , Macaca mulatta , Protein Binding , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Tachycardia/chemically induced , Triazoles/chemical synthesis , Triazoles/metabolism , Triazoles/pharmacokinetics , BenzenesulfonamidesABSTRACT
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.
Subject(s)
Adrenergic beta-Agonists/chemical synthesis , Receptors, Adrenergic, beta/metabolism , Administration, Oral , Adrenergic beta-1 Receptor Agonists , Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Dogs , Heart Rate/drug effects , Humans , Macaca mulatta , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta-3 , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Urea/analogs & derivatives , Urea/chemical synthesis , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
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.
Subject(s)
Adrenergic beta-Agonists/chemical synthesis , Cyclopentanes/chemical synthesis , Imidazoles/chemical synthesis , Receptors, Adrenergic, beta/metabolism , Adrenergic beta-1 Receptor Agonists , Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , Dose-Response Relationship, Drug , Heart Rate/drug effects , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Macaca mulatta , Receptors, Adrenergic, beta/drug effects , Receptors, Adrenergic, beta-3 , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Receptors, Adrenergic, beta/drug effects , Sulfonamides/pharmacology , Adipose Tissue, Brown/drug effects , Animals , CHO Cells , Cricetinae , Female , Heart Rate/drug effects , Humans , Lipolysis/drug effects , Macaca mulatta , Male , Propanolamines/pharmacology , Receptors, Adrenergic, beta-3ABSTRACT
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.
Subject(s)
Adrenergic beta-Agonists/chemical synthesis , Receptors, Adrenergic, beta/drug effects , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Drug Design , Humans , Molecular Conformation , Molecular Structure , Receptors, Adrenergic, beta/physiology , Receptors, Adrenergic, beta-1/drug effects , Receptors, Adrenergic, beta-2/drug effects , Receptors, Adrenergic, beta-3 , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
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.