Water-soluble PDE4 inhibitors for the treatment of dry eye

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 9; pp. 2928 - 2932
• Main Authors: Govek, Steven P., Oshiro, Guy, Anzola, John V., Beauregard, Clay, Chen, Jasmine, Coyle, Avery R., Gamache, Daniel A., Hellberg, Mark R., Hsien, Jennifer N., Lerch, Julia M., Liao, John C., Malecha, James W., Staszewski, Lena M., Thomas, David J., Yanni, John M., Noble, Stewart A., Shiau, Andrew K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-05-2010; Elsevier
• Subjects: 4-Aminopyridine - analogs & derivatives; 4-Aminopyridine - chemical synthesis; 4-Aminopyridine - chemistry; 4-Aminopyridine - therapeutic use; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Binding Sites; Biological and medical sciences; Computer Simulation; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - therapeutic use; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Disease Models, Animal; Dry eye; Dry Eye Syndromes - drug therapy; Eye; Medical sciences; PDE4; PDE4 inhibitor; Pharmacology. Drug treatments; Phosphodiesterase 4 Inhibitors; Rabbits; Rats; Water - chemistry; Dry eye; PDE4; PDE4 inhibitor; Rat; Nitrogen heterocycle; Rabbit; Esterases; Phosphoric diester hydrolases; Oxygen heterocycle; Modeling; Pyridine derivatives; Phosphodiesterase 4 inhibitor; Structure activity relation; Chlorine Organic compounds; Molecular model; Bicyclic compound; Aromatic compound; Enzyme; Rodentia; Antiinflammatory agent; Enzyme inhibitor; Aminoether; Lactone; Inhibitor enzyme complex; Lagomorpha; In vitro; Water soluble compound; In vivo; Eye disease; Vertebrata; Mammalia; Treatment; Animal; Tertiary amine; Hydrolases; 3',5'-cyclic AMP phosphodiesterase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.023

The development of a novel series of water-soluble PDE4 inhibitors led to the discovery of coumarin
18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.
PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin
18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.