Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Jiwon Seo, Pavel Martásek, Linda J. Roman, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-amino)ethylamino]pentyl}-N′-nitroguanidine (l-Arg(NO2)-l-Dbu-NH2 (1) and 4-N-(Nω-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), a series of descarboxamide analogues was designed and synthesized (3-7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. Nα-Methylated analogues (8-11) also were prepared for increased lipophilicity of the inhibitors, but they had 4- to 5-fold weaker binding affinity compared to their parent compounds.

Original languageEnglish (US)
Pages (from-to)1928-1938
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number5
DOIs
StatePublished - Mar 1 2007

Keywords

  • Aminopiperidines
  • Aminopyrrolidines
  • Enzyme inhibitors
  • Neuronal nitric oxide synthase
  • Selective inhibition

ASJC Scopus subject areas

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

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