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Boron‐based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center
Author(s) -
Freund Yvonne R.,
Akama Tsutomu,
Alley M.R.K.,
Antunes Joana,
Dong Chen,
Jarnagin Kurt,
Kimura Richard,
Nieman James A.,
Maples Kirk R.,
Plattner Jacob J.,
Rock Fernando,
Sharma Rashmi,
Singh Rajeshwar,
Sanders Virginia,
Zhou Yasheen
Publication year - 2012
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2012.07.058
Subject(s) - chemistry , bimetal , phosphodiesterase , in vitro , enzyme , boron , catechol , biochemistry , stereochemistry , combinatorial chemistry , organic chemistry
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‐α, IL‐2, IFN‐γ, 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.