Analogues of 2-aminopyridine-based selective inhibitors of neuronal nitric oxide synthase with increased bioavailability

Graham R. Lawton, Hantamalala Ralay Ranaivo, Laura K. Chico, Haitao Ji, Fengtian Xue, Pavel Martásek, Linda J. Roman, D. Martin Watterson, Richard B. Silverman

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2371-2380
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number6
DOIs
StatePublished - Mar 15 2009

Keywords

  • Aminopyridine
  • Bioavailability
  • Blood-brain barrier
  • Ether
  • Neuronal nitric oxide synthase
  • Neuronal nitric oxide synthase inhibitors

ASJC Scopus subject areas

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

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