title: Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).
abstract: PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3'5' adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, CMVLS, Glasgow University, Glasgow G12 8QQ, UK.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Cameron
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Coleman
authors.forename: Jon P
authors.initials: JP
authors.lastname: Day
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Yalla
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D050886:HSP20 Heat-Shock Proteins; D007527:Isoenzymes; D058988:Phosphodiesterase 4 Inhibitors; D044005:Tetrahydroisoquinolines; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C058302:moexipril