Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

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• 作者：Kristin Jansen Labby^a ; Fengtian Xue^a ; ^&dagger ; ; James M. Kraus^a ; Haitao Ji^a ; ^&Dagger ; ; Jan Mataka^a ; Huiying Li^b ; Pavel Martá ; sek^c ; ^d ; Linda J. Roman^c ; Thomas L. Poulos^b ; ^{poulos@uci.edu} ; Richard B. Silverman^a ; ^{Agman@chem.northwestern.edu}
• 关键词：CNS ; central nervous system ; NO ; nitric oxide ; nNOS ; neuronal nitric oxide synthase ; eNOS ; endothelial nitric oxide synthase ; iNOS ; inducible nitric oxide synthase ; BBB ; blood&ndash ; brain barrier ; H-bond ; hydrogen bond ; l-NNA ; l-N-nitroarginine ; H4B ; tetr
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 April, 2012
• 卷：20
• 期：7
• 页码：2435-2443
• 文件大小：832 K

摘要

Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.