Abstract
2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry*
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / therapeutic use
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Benzeneacetamides / chemistry*
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Benzeneacetamides / metabolism
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Benzeneacetamides / therapeutic use
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Binding Sites
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Catalytic Domain
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Crystallography, X-Ray
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Cyclic S-Oxides / chemistry*
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Cyclic S-Oxides / metabolism
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Cyclic S-Oxides / therapeutic use
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Humans
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Lipopolysaccharides / toxicity
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Lung Diseases / drug therapy
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Lung Diseases / pathology
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Mice
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Phosphodiesterase 4 Inhibitors / chemistry*
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Phosphodiesterase 4 Inhibitors / metabolism
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Phosphodiesterase 4 Inhibitors / therapeutic use
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Protein Binding
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / therapeutic use
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Spleen / cytology
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Spleen / metabolism
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Benzeneacetamides
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Cyclic S-Oxides
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Lipopolysaccharides
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Phosphodiesterase 4 Inhibitors
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Pyrimidines
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Tumor Necrosis Factor-alpha
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, mouse
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pyrimidine