Triazine-Based Vanilloid 1 Receptor Open Channel Blockers: Design, Synthesis, Evaluation, and SAR Analysis

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• 作者：Miquel Vidal-Mosquera ; Asia Fern谩ndez-Carvajal ; Alejandra Moure ; Pierluigi Valente ; Rosa Planells-Cases ; Jos茅 M. Gonz谩lez-Ros ; Jordi Bujons ; Antonio Ferrer-Montiel ; Angel Messeguer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 10, 2011
• 年：2011
• 卷：54
• 期：21
• 页码：7441-7452
• 全文大小：1018K
• 年卷期：v.54,no.21(November 10, 2011)
• ISSN：1520-4804

文摘

The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the development of which will require identification of new pharmacophore scaffolds. Uncompetitive antagonists acting as open-channel blockers might serve as activity-dependent blockers that preferentially modulate the activity of overactive channels, thus displaying fewer side effects than their competitive counterparts. Herein we report the design, synthesis, biological evaluation, and SAR analysis of a family of triazine-based compounds acting as TRPV1 uncompetitive antagonists. We identified the triazine 8aA as a potent, pure antagonist that inhibits TRPV1 channel activity with nanomolar efficacy and strong voltage dependency. It represents a new class of activity-dependent TRPV1 antagonists and may serve as the basis for lead optimization in the development of new analgesics.