Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)

Cameron, R.T., Coleman, R.G., Day, J.P., Yalla, K.C., Houslay, M.D., Adams, D.R., Shoichet, B.K. and Baillie, G.S. (2013) Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4). Biochemical Pharmacology, 85(9), pp. 1297-1305. (doi:10.1016/j.bcp.2013.02.026) (PMID:23473803) (PMCID:PMC3625111)

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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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Houslay, Professor Miles and Day, Dr Jonathan and Yalla, Dr Krishna and Cameron, Mr Ryan
Authors: Cameron, R.T., Coleman, R.G., Day, J.P., Yalla, K.C., Houslay, M.D., Adams, D.R., Shoichet, B.K., and Baillie, G.S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Biochemical Pharmacology
Publisher:Elsevier
ISSN:0006-2952
ISSN (Online):1873-2968
Published Online:05 March 2013
Copyright Holders:Copyright © 2013 Elsevier Inc.
First Published:First published in Biochemical Pharmacology 85(9): 1297-1305
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES