Potent and Selective Conformationally Restricted Neuronal Nitric Oxide Synthase Inhibitors

José A. Gómez-Vidal, Pavel Martásek, Linda J. Roman, Richard B. Silverman

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Selective inhibition of the isoforms of nitric oxide synthase (NOS) in pathologically elevated synthesis of nitric oxide has great therapeutic potential. We previously reported nitroarginine-containing dipeptide amides (Huang, H.; Martasek, P.; Roman, L. J.; Masters, B. S. S.; Silverman, R. B. J. Med. Chem. 1999, 42, 3147) and some peptidomimetic analogues (Huang, H.; Martasek, P.; Roman, L. J.; Silverman, R. B. J. Med. Chem. 2000, 43, 2938) as potent and selective inhibitors of neuronal NOS (nNOS). Here we report conformationally restricted dipeptides derived from the dipeptide L-Arg NO2-L-Dbu-NH2 (8). The selectivities for nNOS over endothelial NOS and inducible NOS of the most potent nNOS inhibitor (10a) among these compounds are comparable to that of the parent compound. An unsubstituted amide bond is necessary for potency against nNOS. The stereochemistry of compound 10a was optimum for potency and selectivity and thus provides the binding conformation of the parent compound with nNOS.

Original languageEnglish (US)
Pages (from-to)703-710
Number of pages8
JournalJournal of Medicinal Chemistry
Volume47
Issue number3
DOIs
StatePublished - Jan 29 2004

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Nitric Oxide Synthase Type I
Dipeptides
Amides
Peptidomimetics
Stereochemistry
Nitric Oxide Synthase Type III
Nitroarginine
Nitric Oxide Synthase Type II
Nitric Oxide Synthase
Conformations
Nitric Oxide
Protein Isoforms
Therapeutics

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Potent and Selective Conformationally Restricted Neuronal Nitric Oxide Synthase Inhibitors. / Gómez-Vidal, José A.; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 47, No. 3, 29.01.2004, p. 703-710.

Research output: Contribution to journalArticle

Gómez-Vidal, José A. ; Martásek, Pavel ; Roman, Linda J. ; Silverman, Richard B. / Potent and Selective Conformationally Restricted Neuronal Nitric Oxide Synthase Inhibitors. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 3. pp. 703-710.
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