title: Novel heterocyclic-fused pyridazinones as potent and selective phosphodiesterase IV inhibitors.
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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Firenze, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: M P
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: C
authors.initials: C
authors.lastname: Castellana
authors.forename: J M
authors.initials: JM
authors.lastname: Palacios
authors.forename: J
authors.initials: J
authors.lastname: Beleta
authors.forename: T
authors.initials: T
authors.lastname: Doménech
authors.forename: V
authors.initials: V
authors.lastname: Segarra
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000302:isolation & purification; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D020889:Rolipram; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram