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

• Published in: Journal of medicinal chemistry Vol. 43; no. 4; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.02.2000; Amer Chemical Soc
• 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; Chemistry, Medicinal; 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; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Recombinant Proteins - antagonists & inhibitors; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - enzymology; Science & Technology; Structure-Activity Relationship; Thiadiazines - chemical synthesis; Thiadiazines - chemistry; Thiadiazines - pharmacology; DESIGN; CAMP-SPECIFIC PHOSPHODIESTERASE; IDENTIFICATION; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; CLONING; SACCHAROMYCES-CEREVISIAE; Human; Sulfur nitrogen heterocycle; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Isozyme; Enzyme inhibitor; Esterases; Selectivity; Phosphoric diester hydrolases; Tricyclic compound; In vitro; Structure activity relation; Chlorine Organic compounds; Bicyclic compound; Hydrolases; Aromatic compound; Recombinant protein; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990382n

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.