Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma

He Huang, Huiying Li, Sun Yang, Georges Chreifi, Pavel Martásek, Linda J. Roman, Frank L. Meyskens, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Selective inhibitors of neuronal nitric oxide synthase (nNOS) are regarded as valuable and powerful agents with therapeutic potential for the treatment of chronic neurodegenerative pathologies and human melanoma. Here, we describe a novel hybrid strategy that combines the pharmacokinetically promising thiophene-2-carboximidamide fragment and structural features of our previously reported potent and selective aminopyridine inhibitors. Two inhibitors, 13 and 14, show low nanomolar inhibitory potency (Ki = 5 nM for nNOS) and good isoform selectivities (nNOS over eNOS [440- and 540-fold, respectively] and over iNOS [260- and 340-fold, respectively]). The crystal structures of these nNOS-inhibitor complexes reveal a new hot spot that explains the selectivity of 14 and why converting the secondary to tertiary amine leads to enhanced selectivity. More importantly, these compounds are the first highly potent and selective nNOS inhibitory agents that exhibit excellent in vitro efficacy in melanoma cell lines.

Original languageEnglish (US)
Pages (from-to)686-700
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
StatePublished - Feb 13 2014

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Thiophenes
Nitric Oxide Synthase Type I
Melanoma
Aminopyridines
Amines
Protein Isoforms
Pathology
Cell Line

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. / Huang, He; Li, Huiying; Yang, Sun; Chreifi, Georges; Martásek, Pavel; Roman, Linda J.; Meyskens, Frank L.; Poulos, Thomas L.; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 57, No. 3, 13.02.2014, p. 686-700.

Research output: Contribution to journalArticle

Huang, H, Li, H, Yang, S, Chreifi, G, Martásek, P, Roman, LJ, Meyskens, FL, Poulos, TL & Silverman, RB 2014, 'Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma', Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 686-700. https://doi.org/10.1021/jm401252e
Huang, He ; Li, Huiying ; Yang, Sun ; Chreifi, Georges ; Martásek, Pavel ; Roman, Linda J. ; Meyskens, Frank L. ; Poulos, Thomas L. ; Silverman, Richard B. / Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 3. pp. 686-700.
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AU - Martásek, Pavel

AU - Roman, Linda J.

AU - Meyskens, Frank L.

AU - Poulos, Thomas L.

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