Discovery of triazines as selective PDE4B versus PDE4D inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Hagen, Timothy J.¹  Mo, Xuesheng²  Burgin, Alex B.³  Fox, David, III³  Zhang, Zheng¹  Gurney, Mark E.^2,4 

[1] No Illinois Univ, Dept Chem & Biochem, De Kalb, IL 60115 USA

[2] Tetra Discovery Partners LLC, Grand Rapids, MI USA

[3] Beryllium, Bainbridge Isl, WA 98110 USA

[4] W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA

关键词: PDE4 inhibitor;    PDE4B;    PDE4D;    Crystallography;    Triazine;   

DOI  :  10.1016/j.bmcl.2014.06.002

来源: Elsevier

【 摘 要 】

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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