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

Qing Jing, Huiying Li, Georges Chreifi, Linda J. Roman, Pavel Martásek, Thomas L. Poulos*, Richard B. Silverman

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5674-5679
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2013

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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