ArticleJournal of medicinal chemistry2014
Potent and selective double-headed thiophene-2-carboximidamide inhibitors of neuronal nitric oxide synthase for the treatment of melanoma.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Potent, Selective, and Brain Penetrant Ether-Linked 2-Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability.Journal of medicinal chemistry · 2026Article
- New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.Journal of medicinal chemistry · 2026Article
- Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Targeting Neuronal Nitric Oxide Synthase (nNOS) as a Novel Approach to Enhancing the Anti-Melanoma Activity of Immune Checkpoint Inhibitors.Pharmaceutics · 2025Article
- Stigmasterol Exerts an Anti-Melanoma Property through Down-Regulation of Reactive Oxygen Species and Programmed Cell Death Ligand 1 in Melanoma Cells.Antioxidants (Basel, Switzerland) · 2024Article
- ARL-17477 is a dual inhibitor of NOS1 and the autophagic-lysosomal system that prevents tumor growth in vitro and in vivo.Scientific reports · 2023Article
- A Small Peptide Increases Drug Delivery in Human Melanoma Cells.Pharmaceutics · 2022Article
- Redox-Related Proteins in Melanoma Progression.Antioxidants (Basel, Switzerland) · 2022Article
- Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS).Scientific reports · 2022Article
- Alkynoates as Versatile and Powerful Chemical Tools for the Rapid Assembly of Diverse Heterocycles under Transition-Metal Catalysis: Recent Developments and Challenges.Topics in current chemistry (Cham) · 2021Review
- Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides.Biochemistry · 2018Article
- Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused byMolecules (Basel, Switzerland) · 2018Article
- Nitric oxide synthase and structure-based inhibitor design.Nitric oxide : biology and chemistry · 2017Review
- Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.Journal of medicinal chemistry · 2016Article
- 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.Journal of medicinal chemistry · 2015Article
- Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase.Biochemistry · 2015Article
- Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.Chemistry & biology · 2015Article
- Amyloids, melanins and oxidative stress in melanomagenesis.Experimental dermatology · 2015Article
- Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase.Journal of medicinal chemistry · 2015Article
- Structure-based design of bacterial nitric oxide synthase inhibitors.Journal of medicinal chemistry · 2015Article
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Authors and funding
9 authors.
Funding
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.
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