2024-03-29T05:07:29Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/882032020-08-12T13:37:25Zcom_10261_81com_10261_5com_10261_76com_10261_41com_10261_1col_10261_334col_10261_329col_10261_294
Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides: First phosphodiesterase 7 inhibitors
Martínez, Ana
Castro, Ana
Gil, Carmen
Miralpeix, Montserrat
Segarra, Víctor
Doménech, Teresa
Beleta, Jorge
Palacios, José M.
Ryder, Hamish
Miró, Xavier
Bonet-Costa, Carles
Casacuberta, Josep M.
Azorín, Ferran
Piña, Benjamín
Puigdomènech, Pere
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.
2013-12-04T11:34:41Z
2013-12-04T11:34:41Z
2000
2013-12-04T11:34:41Z
artículo
Journal of Medicinal Chemistry 43: 683- 689 (2000)
http://hdl.handle.net/10261/88203
10.1021/jm990382n
eng
closedAccess
American Chemical Society