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Bioorg Med Chem Lett. 2013 Oct 15;23(20):5674-9. doi: 10.1016/j.bmcl.2013.08.034. Epub 2013 Aug 14.

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

Author information

1
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.

Abstract

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 32nM 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.

KEYWORDS:

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

PMID:
23993333
PMCID:
PMC3790268
DOI:
10.1016/j.bmcl.2013.08.034
[Indexed for MEDLINE]
Free PMC Article

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