ABSTRACT
As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Administration, Oral , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Biological Availability , CHO Cells , Cloning, Molecular , Cricetinae , Dogs , Glycerol/blood , Humans , Macaca mulatta , Male , Radioligand Assay , Rats , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacologyABSTRACT
A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Ethanolamines/chemical synthesis , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Structure-Activity Relationship , BenzenesulfonamidesABSTRACT
A series of compounds possessing an N-substituted indoline-5-sulfonamide pharmacophore was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. The SAR of a wide range of urea and heterocyclic substituents is discussed. 4-Octyl thiazole compound 8c was the most potent and selective compound in the series, with 2800-fold selectivity over beta1 binding and 1400-fold selectivity over beta2 binding.
Subject(s)
Adrenergic Agonists/chemical synthesis , Adrenergic Agonists/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Models, Chemical , 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 cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.
Subject(s)
Adrenergic beta-Agonists/chemical synthesis , Propanolamines/chemistry , Propanolamines/chemical synthesis , Receptors, Adrenergic, beta/drug effects , Sulfonamides/chemistry , Sulfonamides/chemical synthesis , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Cloning, Molecular , Drug Design , Humans , Molecular Conformation , Molecular Structure , Propanolamines/pharmacology , Receptors, Adrenergic, beta/physiology , Receptors, Adrenergic, beta-1/drug effects , Receptors, Adrenergic, beta-2/drug effects , Receptors, Adrenergic, beta-3 , Recombinant Proteins/drug effects , Recombinant Proteins/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacology , BenzenesulfonamidesABSTRACT
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.
