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
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
Subject(s)
Coccidiostats/chemical synthesis , Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Protozoan Proteins/antagonists & inhibitors , Pyrroles/chemical synthesis , Animals , Biological Availability , Chickens , Coccidiosis/drug therapy , Coccidiostats/pharmacokinetics , Coccidiostats/pharmacology , Eimeria , Half-Life , Inhibitory Concentration 50 , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of a number of indole GnRH antagonists is described. Oxidation of the pyridine ring nitrogen, combined with alkylation at the two position, led to a compound with an excellent in vitro activity profile as well as oral bioavailability in both rats and dogs.
