期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 6, 页码 2371-2380出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.02.017
关键词
Neuronal nitric oxide synthase; Neuronal nitric oxide synthase inhibitors; Ether; Bioavailability; Blood-brain barrier; Aminopyridine
资金
- National Institutes of Health [GM49725, GM52419]
- Robert A. Welch Foundation [AQ1192]
- MSMT of the Czech Republic [0021620806, 1M0520]
Overproduction of nitric oxide by neuronal nitric oxide synthase ( nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics. Replacement of secondary amines in our lead compound with neutral ether and amide groups was made to increase bioavailability and to determine if the potency and selectivity of the inhibitor would be impacted. An ether analogue has been identified that retains a similar potency and selectivity to that of the lead compound, and shows increased ability to penetrate the blood brain barrier. (C) 2009 Elsevier Ltd. All rights reserved.
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