Discovery of triazines as selective PDE4B versus PDE4D inhibitors

Abstract

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive “closed” conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.

New insights into PDE4B inhibitor selectivity: CoMFA analyses and molecular docking studies

“…Consequently, any detailed consideration about the PDE4B and PDE4D selectivity issue could be addressed only if the X-ray of complete PDE4B and PDE4D isoforms in complex with the same inhibitor were available, especially in the case of contacts with CR3. In our particular case, while 3G45 (PDE4B) and 3G4G (PDE4D) [19] may be used for the study of the binding between UCR2 and inhibitors, only the first two studied scaffolds (group I and II) were co-crystallized with PDE4B including CR3 (PDB code: 4MYQ and 4NW7, respectively) [19,46]. On the other hand, no experimental data on the binding mode of those compounds included in group III were available.…”

“…The PDE4-inhibitory potency of compounds 1-29 (Table 1; group I) [45], 30-47 (Table 1; group II) [46] and 48-85 (Table 1; group III) [47] was measured using recombinant human PDE4B1 and human PDE4D3, human PDE4B and PDE4D, and human PDE4B2 and human PDE4D2, respectively.…”

“…Regarding groups I and II, crystal structures of the most representative compounds within PDE4B are available, as found in 4MYQ [20] and 4NW7 [46] (PDB codes), respectively. In the two X-ray complexes (4MYQ and 4NW7), the PDE4B inhibitor interacts with both the active site and CR3, explaining in this way their selectivity of action between PDE4B and PDE4D.…”

“…Therefore, this work centers on a computational approach performed on three series of selective PDE4B inhibitors collected from the literature [45][46][47], which involves CoMFA analyses to explore the key requirements underlying the selective PDE4B inhibitor behaviour. The effectiveness of CoMFA results was evaluated by subsequent molecular docking studies.…”

Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities

“…Recently a series of triazine derivatives were found to be PDE4B selective inhibitors, which show >100-fold selectivity over the PDE4D isozyme. These PDE4B inhibitors exhibited potent anti-inflammatory effects in vivo and showed less emesis (Hagen et al, 2014; Naganuma et al, 2009). PDE4B inhibition may also have effects on generalized anxiety, which could influence drug craving during abstinence.…”