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Novel Roflumilast Analogs as Soft PDE4 Inhibitors

Novel Roflumilast Analogs as Soft PDE4 Inhibitors

Sandro Boland, Jo Alen, Arnaud Bourin, Karolien Castermans, Nicki Boumans, Laura Panitti, Jessica Vanormelingen, Dirk Leysen, Olivier Defert

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4594-4597.

PMID: 25149511

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245701	PDE4B1 Active human			Price
IAR4245720	PDE4D2 active human			Price

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