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Bioorg Med Chem Lett. 2014 Sep 15;24(18):4594-4597. doi: 10.1016/j.bmcl.2014.07.016. Epub 2014 Jul 12.

Novel Roflumilast analogs as soft PDE4 inhibitors.

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Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium. Electronic address:
Amakem N.V. Agoralaan A bis, 3590 Diepenbeek, Belgium.


PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.


COPD; Esterase; PDE4 inhibitors; SAR; Soft drug

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