Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center
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- 作者：Yvonne R. Freund ; Tsutomu Akama ; M.R.K. Alley ; Joana Antunes ; Chen Dong ; Kurt Jarnagin ; Richard Kimura ; James A. Nieman ; Kirk R. Maples ; Jacob J. Plattner ; Fern ; o Rock ; Rashmi Sharma ; Rajeshwar Singh ; Virginia S ; ers ; Yasheen Zhou
- 关键词：PDE4 ; phosphodiesterase 4
- 刊名：FEBS Letters
- 出版年：2012
- 出版时间：21 September, 2012
- 年：2012
- 卷：586
- 期：19
- 页码：3410-3414
- 全文大小：718 K
文摘
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-¦Á, IL-2, IFN-¦Ã, 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.