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 ben zothieno[3,2-a]-thiadiazine 2,2-dioxides was achieved. The biological data revealed the first heterocyclic family of compounds with PDE 7 inhibitory p roperties appearing to be a new objective for the treatment of T-cell-depen dent disorders. The IC50 values or percent inhibition values of the compoun ds 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 h uman PDE 7. Isoenzyme selectivity PDE 7 versus PDE 4 and PDE 3 was also mea sured. Considering simultaneously inhibition of the three different isoenzy mes, monobenzyl derivatives 15 and 23 showed interesting PDE 7 potency (aro und 10 mu M); although not statistically significant, a trend toward select ivity with respect to PDE 3 and PDE 4 was obtained. Benzothiadiazine 16, al though less potent at PDE 7 (IC50 25 mu M), also showed a trend of selectiv ity toward PDE 3 and PDE 4. These compounds are considered the best leads f or further optimization.