ABSTRACT
A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV K(i)=2nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/pharmacology , Xanthines/pharmacology , Animals , Dipeptidyl Peptidase 4/chemistry , Imidazoles/pharmacology , Kinetics , Models, Molecular , Protease Inhibitors/chemical synthesis , Protein Conformation , Rats , Structure-Activity Relationship , X-Ray Diffraction , Xanthines/chemical synthesisABSTRACT
High throughput screening efforts have identified a novel class of dichloroaniline amide 11beta-HSD1 inhibitors. SAR studies initiated from dichloroaniline 4 focused on retaining the potency and selectivity profile of the lead.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Metabolic Syndrome/drug therapy , Carbenoxolone/chemistry , Carbenoxolone/pharmacology , Enzyme Inhibitors/therapeutic use , Humans , Molecular Conformation , Piperazines/chemistry , Piperazines/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
Subject(s)
Bridged-Ring Compounds/chemical synthesis , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/chemical synthesis , Liver/metabolism , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Bile Acids and Salts/chemistry , Binding Sites , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , CHO Cells , Cells, Cultured , Computer Simulation , Cricetinae , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Type 2/blood , Glucose/biosynthesis , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Models, Molecular , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/physiology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
Biaryl amides derived from a reported series of ureas 1 were evaluated and found to be potent human glucagon receptor antagonists. The benzofuran analogue 6i was administered in Sprague-Dawley rats and blocked the effects of an exogenous glucagon challenge.
Subject(s)
Amides/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Amides/chemistry , Animals , Haplorhini , Humans , Mice , Rats , Rats, Sprague-DawleyABSTRACT
Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.
