N-Arylrolipram derivatives as potent and selective PDE4 inhibitors

• Published in: Bioorganic & medicinal chemistry letters 1998-11, Vol.8 (22), p.3229-3234
• Main Authors: Bacher, Edmond, Boer, Christiene, Bray-French, Katharine, Demnitz, F.W.Joachim, Keller, Thomas H., Mazzoni, Lazzaro, Müller, Thomas, Walker, Christoph
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Animals; Anti-Asthmatic Agents - chemical synthesis; Anti-Asthmatic Agents - pharmacology; Biological and medical sciences; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Immunomodulators; Leukocytes - drug effects; Medical sciences; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Pyrrolidinones - chemical synthesis; Pyrrolidinones - pharmacology; Rats; Rats, Inbred BN; Respiratory system; Rolipram; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(98)00583-6

Derivatization of rolipram led to the identification of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-5-(3-methoxybenzyloxy)-benzoic acid N′, N′-dimethylhydrazide ( 4 ), a potent and selective inhibitor of PDE4, which inhibits the activation of human leukocytes with pIC 50 values in the range of 7.3 – 7.8, and blocks antigen induced eosinophilia in Brown Norway rats at a dose of 1 mg/kg (i.t.). A rolipram derivative was identified which is a potent and selective inhibitor of PDE4 and shows promising activity in cellular assay and in vivo models.