Rhodanine derivatives as novel inhibitors of PDE4

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 6; pp. 2032 - 2037
• Main Authors: Irvine, Mark W., Patrick, Graham L., Kewney, Justin, Hastings, Stuart F., MacKenzie, Simon J.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2008; Elsevier
• Subjects: Asthma; Biological and medical sciences; COPD; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Humans; Medical sciences; Molecular Structure; PDE4 inhibitor; Pharmacology. Drug treatments; Phosphodiesterase 4; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - pharmacology; Respiratory system; Rhodanine; Structure-Activity Relationship; Thiohydantoins - chemical synthesis; Thiohydantoins - pharmacology; Rhodanine; Phosphodiesterase 4; PDE4 inhibitor; Asthma; COPD; Lung disease; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Respiratory disease; Enzyme inhibitor; Esterases; Phosphoric diester hydrolases; In vitro; Structure activity relation; Hydrolases; Bronchus disease; Chronic obstructive pulmonary disease; Obstructive pulmonary disease; Chemical synthesis; Thiazolidine derivatives
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.01.117

The discovery, synthesis and in-vitro activity of a novel series of rhodanine based phosphodiesterase-4 inhibitors (e.g. 3i) is described. The discovery, synthesis and in vitro activity of a novel series of rhodanine based phosphodiesterase-4 (PDE4) inhibitors is described. Structure-activity relationship studies directed toward improving potency led to the development of submicromolar inhibitors 2n and 3i (IC 50 = 0.89 & 0.74 μM). The replacement of rhodanine with structurally related heterocycles was also investigated and led to the synthesis of pseudothiohydantoin 7 (IC 50 = 0.31 μM).