Novel Heterocyclic-Fused Pyridazinones as Potent and Selective Phosphodiesterase IV Inhibitors

• Published in: Journal of medicinal chemistry Vol. 40; no. 10; pp. 1417 - 1421
• Main Authors: Dal Piaz, Vittorio, Giovannoni, Maria Paola, Castellana, Carla, Palacios, José Maria, Beleta, Jorge, Doménech, Teresa, Segarra, Victor
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.05.1997; Amer Chemical Soc
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Chemistry, Medicinal; Cyclic Nucleotide Phosphodiesterases, Type 4; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Guinea Pigs; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphoric Diester Hydrolases - drug effects; Phosphoric Diester Hydrolases - isolation & purification; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridazines - chemistry; Pyridazines - pharmacology; Pyrrolidinones - metabolism; Radioligand Assay; Rats; Rolipram; Science & Technology; Structure-Activity Relationship; BINDING-SITE; H-3 ROLIPRAM; AMP; AFFINITY; BRAIN; DISCOVERY; Sulfur nitrogen heterocycle; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Nitrogen heterocycle; Isozyme; Benzene derivatives; Lactam; Enzyme inhibitor; Esterases; Phosphoric diester hydrolases; In vitro; Structure activity relation; Bicyclic compound; Hydrolases; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970105l

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.