ABSTRACT
3-Aryl-5-phenyl-(1,2,4)-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active in both in vitro and an in vivo mouse pharmacodynamic (PD) model. The synthesis and structure activity relationships are presented.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors , Hydrocarbons, Aromatic , Hypoglycemic Agents , Metabolic Syndrome/drug therapy , Triazoles , Animals , Binding Sites , Disease Models, Animal , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Hydrocarbons, Aromatic/chemical synthesis , Hydrocarbons, Aromatic/pharmacology , Hydrocarbons, Aromatic/therapeutic use , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Inhibitory Concentration 50 , Mice , Models, Chemical , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacology , Triazoles/therapeutic useABSTRACT
3-(Phenylcyclobutyl)-1,2,4-triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). These were active both in vitro and in an in vivo mouse pharmacodynamic (PD) model. Fluorine substitution of the cyclobutane ring improved the pharmacokinetic profile significantly. The synthesis and structure-activity relationships are presented.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Triazoles/pharmacology , Administration, Oral , Animals , Combinatorial Chemistry Techniques , Cortisone/analysis , Cortisone/blood , Disease Models, Animal , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Hydrocortisone/analysis , Hydrocortisone/blood , Mice , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Triazoles/pharmacokineticsABSTRACT
A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.