Journal
FEBS LETTERS
Volume 586, Issue 19, Pages 3410-3414Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.febslet.2012.07.058
Keywords
PDE4; Phenoxybenzoxaborole; Crystal structure; Cytokine inhibition
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We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-alpha, IL-2, IFN-gamma, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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