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New Classes of PDE7 Inhibitors Identified by a Fission Yeast-Based HTS
- Source :
- SLAS Discovery. 15:359-367
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
Abstract
- 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.
- Subjects :
- Lipopolysaccharides
Phosphodiesterase Inhibitors
Allosteric regulation
Anti-Inflammatory Agents
Biochemistry
Article
Analytical Chemistry
Inhibitory Concentration 50
Catalytic Domain
Schizosaccharomyces
High-Throughput Screening Assays
Cyclic AMP
medicine
Humans
Rolipram
Enzyme Assays
Orotic Acid
Cyclic Nucleotide Phosphodiesterases, Type 7
biology
Tumor Necrosis Factor-alpha
Hydrolysis
Phosphodiesterase
biology.organism_classification
Enzyme assay
Yeast
Schizosaccharomyces pombe
biology.protein
Molecular Medicine
Biotechnology
medicine.drug
Subjects
Details
- ISSN :
- 24725552
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- SLAS Discovery
- Accession number :
- edsair.doi.dedup.....b35666307e24d6390e61cf8b9ea33409