Design, Synthesis, and Structure−Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors

Abstract

Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC50 values. The most potent compounds have IC50 values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.

Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi , the Etiological Agent of Chagas' Disease

“…All reagents were purchased from Acros and Aldrich. 3-{1-[3-methoxy-4-(pyridin-2-yloxy)-phenyl]-but-1-enyl}-quinoline (compound 7) was synthesized according to a previously described procedure (37). Microwave heating was performed in the single-mode microwave cavity of a Discover Synthesis system (CEM Co.), and all microwave reactions were conducted in heavy-walled glass vials sealed with Teflon septa.…”

“…Compounds 2a, 3b, 4a and b, and 5a to u were synthesized according to procedures described earlier (37).…”

“…We previously worked on developing inhibitors for mammalian PDE4 (37). T. cruzi PDEC has 28% sequence identity with human PDE4B (PDB entry 1XMY), for which the crystal structure is available (see Fig.…”

“…Because of the structural similarity between the homology model of PDEC and the PDE4B crystal structure, in our initial effort to search for T. cruzi PDEC inhibitors, we tested a number of compounds generated for our PDE4 inhibition project (37). The synthesis of most of these compounds has been described (37).…”

“…We report here the testing of several compounds, initially designed as potential PDE4 inhibitors (37) or obtained by virtual screening, against T. cruzi amastigote growth and TcrPDEC activities. In addition, we report that several of these compounds inhibit TcPDEC in vivo, as shown by their effects on cyclic AMP levels and on the regulatory volume decrease after these parasites are subjected to hyposmotic stress, providing chemical validation for this potential drug target.…”