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

Ryan T. Cameron, Ryan G. Coleman, Jon P. Day, Krishna C. Yalla, Miles D. Houslay, David R. Adams, Brian K. Shoichet, George S. Baillie

Research output: Contribution to journalArticle

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. (C) 2013 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)1297-1305
Number of pages9
JournalBiochemical Pharmacology
Volume85
Issue number9
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Protein kinase A (PKA), PDE4
  • Cyclic 3 ' 5 ' adenosine monophosphate (cAMP)
  • DRUGS
  • PHOSPHORYLATION
  • OBSTRUCTIVE PULMONARY-DISEASE
  • ROFLUMILAST
  • ACTIVATION
  • Catechol ether
  • CONVERTING-ENZYME
  • RECEPTOR
  • TARGET
  • CHEMISTRY
  • Phosphodiesterase inhibitor
  • PROTEIN-KINASE

Cite this

Cameron, Ryan T. ; Coleman, Ryan G. ; Day, Jon P. ; Yalla, Krishna C. ; Houslay, Miles D. ; Adams, David R. ; Shoichet, Brian K. ; Baillie, George S. / Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4). In: Biochemical Pharmacology. 2013 ; Vol. 85, No. 9. pp. 1297-1305.
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Cameron, RT, Coleman, RG, Day, JP, Yalla, KC, Houslay, MD, Adams, DR, Shoichet, BK & Baillie, GS 2013, 'Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)', Biochemical Pharmacology, vol. 85, no. 9, pp. 1297-1305. https://doi.org/10.1016/j.bcp.2013.02.026

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4). / Cameron, Ryan T.; Coleman, Ryan G.; Day, Jon P.; Yalla, Krishna C.; Houslay, Miles D.; Adams, David R.; Shoichet, Brian K.; Baillie, George S.

In: Biochemical Pharmacology, Vol. 85, No. 9, 01.05.2013, p. 1297-1305.

Research output: Contribution to journalArticle

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AU - Cameron, Ryan T.

AU - Coleman, Ryan G.

AU - Day, Jon P.

AU - Yalla, Krishna C.

AU - Houslay, Miles D.

AU - Adams, David R.

AU - Shoichet, Brian K.

AU - Baillie, George S.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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. (C) 2013 Elsevier Inc. All rights reserved.

AB - 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. (C) 2013 Elsevier Inc. All rights reserved.

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KW - Cyclic 3 ' 5 ' adenosine monophosphate (cAMP)

KW - DRUGS

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KW - OBSTRUCTIVE PULMONARY-DISEASE

KW - ROFLUMILAST

KW - ACTIVATION

KW - Catechol ether

KW - CONVERTING-ENZYME

KW - RECEPTOR

KW - TARGET

KW - CHEMISTRY

KW - Phosphodiesterase inhibitor

KW - PROTEIN-KINASE

U2 - 10.1016/j.bcp.2013.02.026

DO - 10.1016/j.bcp.2013.02.026

M3 - Article

VL - 85

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JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

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ER -