New classes of PDE7 inhibitors identified by a fission yeast-based HTS.
Studies of the phosphodiesterase PDE7 family are impeded by there being only one commercially available PDE7 inhibitor, BRL50481. The authors have employed a high-throughput screen of commercial chemical libraries, using a fission yeast-based assay, to identify PDE7 inhibitors that include steroids, podocarpanes, and an unusual heterocyclic compound, BC30. In vitro enzyme assays measuring the potency of BC30 and 2 podocarpanes, in comparison with BRL50481, produce data consistent with those from yeast-based assays. In other enzyme assays, BC30 stimulates the PDE4D catalytic domain but not full-length PDE4D2, suggesting an allosteric site of action. BC30 significantly enhances the anti-inflammatory effect of the PDE4 inhibitor rolipram as measured by release of tumor necrosis factor alpha from activated monocytes. These studies introduce several new PDE7 inhibitors that may be excellent candidates for medicinal chemistry because of the requirements for drug-like characteristics placed on them by the nature of the yeast-based screen.
Biology Department, Boston College, Chestnut Hill, Massachusetts, USA.
Manal A
MA
Alaamery
Arlene R
AR
Wyman
F Douglas
FD
Ivey
Christina
C
Allain
Didem
D
Demirbas
Lili
L
Wang
Ozge
O
Ceyhan
Charles S
CS
Hoffman
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D057075:Enzyme Assays; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D009963:Orotic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009963:Orotic Acid; C001242:5-fluoroorotic acid; D000242:Cyclic AMP; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7