Abstract
A series of 6-aryl-4,5-heterocyclic-fused pyridazinones were designed and synthesized as selective phosphodiesterase (PDE) IV inhibitors. Biological evaluation of these compounds demonstrated a good selectivity profile toward the PDE IV family and greatly attenuated affinity for the Rolipram high-affinity binding site that seems to be responsible for undesiderable side effects. Structure-activity relationships (SARs) studies showed that the presence of an ethyl group at pyridazine N-2 is associated with the best potency and selectivity profile.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
3',5'-Cyclic-AMP Phosphodiesterases*
-
Animals
-
Brain / drug effects
-
Brain / metabolism
-
Cyclic Nucleotide Phosphodiesterases, Type 4
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Guinea Pigs
-
Magnetic Resonance Spectroscopy
-
Phosphoric Diester Hydrolases / drug effects*
-
Phosphoric Diester Hydrolases / isolation & purification
-
Pyridazines / chemistry
-
Pyridazines / pharmacology*
-
Pyrrolidinones / metabolism
-
Radioligand Assay
-
Rats
-
Rolipram
-
Structure-Activity Relationship
Substances
-
Enzyme Inhibitors
-
Pyridazines
-
Pyrrolidinones
-
Phosphoric Diester Hydrolases
-
3',5'-Cyclic-AMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 4
-
Rolipram