Effect of potential amine prodrugs of selective neuronal nitric oxide synthase inhibitors on blood-brain barrier penetration

Richard B. Silverman, Graham R. Lawton, Hantamalala Ralay Ranaivo, Laura K. Chico, Jiwon Seo, D. Martin Watterson

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the uses of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective for CNS applications.

Original languageEnglish (US)
Pages (from-to)7593-7605
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number21
DOIs
StatePublished - Nov 1 2009

Keywords

  • Amide prodrug
  • Amine prodrug
  • Azide prodrug
  • Blood-brain barrier
  • Carbamate prodrug
  • Neuronal nitric oxide synthase
  • Neuronal nitric oxide synthase inhibitor
  • Organic azide
  • Prodrug

ASJC Scopus subject areas

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

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