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
Adamantyl triazoles were identified as selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). They are active both in in vitro and in in vivo pharmacodynamic models. The synthesis and structure-activity relationships of these inhibitors are presented.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Adamantane/chemical synthesis , Adamantane/pharmacokinetics , Adamantane/pharmacology , Animals , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Metabolic Syndrome/drug therapy , Mice , Pharmacokinetics , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacologyABSTRACT
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.
Subject(s)
Receptors, Glucocorticoid/metabolism , Animals , Cells, Cultured , Humans , In Vitro Techniques , Ligands , MiceABSTRACT
A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.
