Potent and selective neuronal nitric oxide synthase inhibitors with improved cellular permeability

Fengtian Xue, Jianguo Fang, William W. Lewis, Pavel Martásek, Linda J. Roman, Richard B. Silverman

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Recently, a series of potent and selective neuronal nitric oxide synthase inhibitors containing two basic nitrogen atoms was reported (Ji, H.; Stanton, B. Z.; Igarashi, J.; Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. J. Am. Chem. Soc. 2008, 130, 3900-3914). In an effort to improve their bioavailability, three compounds (2a-c) were designed with electron-withdrawing groups near one of the basic nitrogen atoms to lower its pKa. Inhibition studies with these compounds showed that two of them not only retained most of the potency and selectivity of the best analogue of the earlier series, but also showed improved membrane permeability based on data from a cell-based assay.

Original languageEnglish (US)
Pages (from-to)554-557
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number2
DOIs
StatePublished - Jan 15 2010

Keywords

  • Increased membrane permeability
  • Neuronal nitric oxide synthase
  • Selective inhibitors
  • pK

ASJC Scopus subject areas

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

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