Benzyl Derivatives of 2,1,3-Benzo- and Benzothieno[3,2-a]thiadiazine 2,2-Dioxides:  First Phosphodiesterase 7 Inhibitors

The synthesis of a new family of benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell-depend...

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Published in:Journal of medicinal chemistry 2000-02, Vol.43 (4), p.683-689
Main Authors: Martínez, Ana, Castro, Ana, Gil, Carmen, Miralpeix, Montserrat, Segarra, Victor, Doménech, Teresa, Beleta, Jorge, Palacios, Jose M, Ryder, Hamish, Miró, Xavier, Bonet, Carles, Casacuberta, Josep M, Azorín, Ferran, Piña, Benjamí, Puigdoménech, Pere
Format: Article
Language:English
Subjects:
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
Benzothiadiazines - chemical synthesis
Benzothiadiazines - chemistry
Benzothiadiazines - pharmacology
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cyclic Nucleotide Phosphodiesterases, Type 4
Cyclic Nucleotide Phosphodiesterases, Type 7
Drug Evaluation, Preclinical
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Isoenzymes - antagonists & inhibitors
Medical sciences
Pharmacology. Drug treatments
Recombinant Proteins - antagonists & inhibitors
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - enzymology
Structure-Activity Relationship
Thiadiazines - chemical synthesis
Thiadiazines - chemistry
Thiadiazines - pharmacology
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Summary:The synthesis of a new family of benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory properties appearing to be a new objective for the treatment of T-cell-dependent disorders. The IC50 values or percent inhibition values of the compounds against PDE 7 were calculated by testing them against human recombinant PDE 7 expressed in S. cerevisiae. In this expression system the only cyclic nucleotide hydrolyzing activity present in cell extracts corresponded to human PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also measured. Considering simultaneously inhibition of the three different isoenzymes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (around 10 μM); although not statistically significant, a trend toward selectivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, although less potent at PDE 7 (IC50 = 25 μM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990382n