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Bioorg Med Chem. 2013 Mar 1;21(5):1333-43. doi: 10.1016/j.bmc.2012.12.019. Epub 2012 Dec 22.

Cyclopropyl- and methyl-containing inhibitors of neuronal nitric oxide synthase.

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  • 1Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA.

Abstract

Inhibitors of neuronal nitric oxide synthase have been proposed as therapeutics for the treatment of different types of neurological disorders. On the basis of a cis-3,4-pyrrolidine scaffold, a series of trans-cyclopropyl- and methyl-containing nNOS inhibitors have been synthesized. The insertion of a rigid electron-withdrawing cyclopropyl ring decreases the basicity of the adjacent amino group, which resulted in decreased inhibitory activity of these inhibitors compared to the parent compound. Nonetheless, three of them exhibited double-digit nanomolar inhibition with high nNOS selectivity on the basis of in vitro enzyme assays. Crystal structures of nNOS and eNOS with these inhibitors bound provide a basis for detailed structure-activity relationship (SAR) studies. The conclusions from these studies will be used as a guide in the future development of selective NOS inhibitors.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID:
23352768
[PubMed - indexed for MEDLINE]
PMCID:
PMC3574199
Free PMC Article

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