title: Benzyl derivatives of 2,1,3-benzo- and benzothieno[3,2-a]thiadiazine 2,2-dioxides: first phosphodiesterase 7 inhibitors.
abstract: 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 IC(50) 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 microM); 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 (IC(50) = 25 microM), also showed a trend of selectivity toward PDE 3 and PDE 4. These compounds are considered the best leads for further optimization.
authors.affiliation: Instituto de Química Médica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain. iqmam06@pinar2.csic.es
authors.forename: A
authors.initials: A
authors.lastname: Martínez
authors.forename: A
authors.initials: A
authors.lastname: Castro
authors.forename: C
authors.initials: C
authors.lastname: Gil
authors.forename: M
authors.initials: M
authors.lastname: Miralpeix
authors.forename: V
authors.initials: V
authors.lastname: Segarra
authors.forename: T
authors.initials: T
authors.lastname: Doménech
authors.forename: J
authors.initials: J
authors.lastname: Beleta
authors.forename: J M
authors.initials: JM
authors.lastname: Palacios
authors.forename: H
authors.initials: H
authors.lastname: Ryder
authors.forename: X
authors.initials: X
authors.lastname: Miró
authors.forename: C
authors.initials: C
authors.lastname: Bonet
authors.forename: J M
authors.initials: JM
authors.lastname: Casacuberta
authors.forename: F
authors.initials: F
authors.lastname: Azorín
authors.forename: B
authors.initials: B
authors.lastname: Piña
authors.forename: P
authors.initials: P
authors.lastname: Puigdoménech
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001581:Benzothiadiazines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D013829:Thiadiazines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7