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Phosphodiesterases as Drug Targets pp 167–192Cite as

Small Molecule Allosteric Modulators of Phosphodiesterase 4

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 204))

Abstract

Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis-capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices.

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Authors and Affiliations

  1. Tetra Discovery Partners, Grand Rapids, MI, USA

    Mark E. Gurney

  2. Emerald BioStructures, Bainbridge Island, WA, USA

    Alex B. Burgin & Lance J. Stewart

  3. deCODE genetics, Reykjavik, Iceland

    Olafur T. Magnusson

Authors
  1. Mark E. Gurney
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  2. Alex B. Burgin
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  3. Olafur T. Magnusson
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  4. Lance J. Stewart
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Corresponding author

Correspondence to Mark E. Gurney .

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Editors and Affiliations

  1. School of Medicine, Dept. Molecular Physiology & Biophysics, Vanderbilt University, Light Hall 702, Nashville, 37232-0615, Tennessee, USA

    Sharron H. Francis

  2. HSW 1656, Center for Reproductive Sciences, Parnassus Avenue 513, San Francisco, 94143-0556, California, USA

    Marco Conti

  3. Wolfson Building, University of Glasgow, Glasgow, G12 8QQ, United Kingdom

    Miles D. Houslay

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Gurney, M.E., Burgin, A.B., Magnusson, O.T., Stewart, L.J. (2011). Small Molecule Allosteric Modulators of Phosphodiesterase 4. In: Francis, S., Conti, M., Houslay, M. (eds) Phosphodiesterases as Drug Targets. Handbook of Experimental Pharmacology, vol 204. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17969-3_7

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