Chiral linkers to improve selectivity of double-headed neuronal nitric oxide synthase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Jing, Qing^1,2  Li, Huiying³  Chreifi, Georges³  Roman, Linda J.⁴  Martasek, Pavel^4,5  Poulos, Thomas L.³  Silverman, Richard B.^1,2 

[1] Northwestern Univ, Chem Life Proc Inst, Dept Mol Biosci, Dept Chem, Evanston, IL 60208 USA

[2] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Evanston, IL 60208 USA

[3] Univ Calif Irvine, Dept Mol Biol & Biochem Pharmaceut Sci & Chem, Irvine, CA 92697 USA

[4] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78384 USA

[5] Charles Univ Prague, Fac Med 1, Dept Pediat, Prague, Czech Republic

关键词: Neuronal nitric oxide synthase;    Inhibition;    Chiral molecules;    Double-headed inhibitors;    Crystallography;   

DOI  :  10.1016/j.bmcl.2013.08.034

来源: Elsevier

【 摘 要 】

To develop potent and selective nNOS inhibitors, new double-headed molecules with chiral linkers that derive from natural amino acids or their derivatives have been designed. The new structures contain two ether bonds, which greatly simplifies the synthesis and accelerates structure optimization. Inhibitor (R)-6b exhibits a potency of 32 nM against nNOS and is 475 and 244 more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 6b and the two heme propionates in nNOS, but not eNOS, is the structural basis for its high selectivity. This work demonstrates the importance of stereochemistry in this class of molecules, which significantly influences the potency and selectivity of the inhibitors. The structure-activity information gathered here provides a guide for future structure optimization. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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