Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Four new conformationally restricted analogues of a potent and selective neuronal nitric oxide synthase inhibitor, L-nitroargininyl-L-2,4- diaminobutyramide (1), have been synthesized. Nα-Methyl and Nα-benzyl derivatives (3 and 4, respectively) of 4-N-(L-ArgNO2)-trans-4-amino-L-prolineamide (2) are also selective inhibitors, but the potency and selectivity of 3 are weak. Analogue 4 has only one-third the potency and one-half to one-third the selectivity of 2 against iNOS (inducible nitric oxide synthase) and eNOS (endothelial nitric oxide synthase), respectively. 3-N-(L-ArgNO2)-trans-3-amino-L-prolineamide (6) is as potent an inhibitor of nNOS (neuronal nitric oxide synthase) as 2; selectivity for nNOS over iNOS is half of that for 2, but the selectivity for nNOS over eNOS is almost double that for 2. The corresponding cis-isomer (5) is a weak inhibitor of nNOS. These results are supported by computer modeling.

Original languageEnglish (US)
Pages (from-to)6254-6263
Number of pages10
JournalJournal of Medicinal Chemistry
Volume49
Issue number21
DOIs
StatePublished - Oct 2006

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Nitric Oxide Synthase Type I
Dipeptides
Amides
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Isomers
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors. / Ji, Haitao; Gómez-Vidal, José A.; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 49, No. 21, 10.2006, p. 6254-6263.

Research output: Contribution to journalArticle

Ji, Haitao ; Gómez-Vidal, José A. ; Martásek, Pavel ; Roman, Linda J. ; Silverman, Richard B. / Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 21. pp. 6254-6263.
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