Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists

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• 作者：Arthur Gomtsyan ; Robert G. Schmidt ; Erol K. Bayburt ; Gregory A. Gfesser ; Eric A. Voight ; Jerome F. Daanen ; Diana L. Schmidt ; Marlon D. Cowart ; Huaqing Liu ; Robert J. Altenbach ; Michael E. Kort ; Bruce Clapham ; Phil B. Cox ; Anurupa Shrestha ; Rodger Henry ; David N. Whittern ; Regina M. Reilly ; Pamela S. Puttfarcken ; Jill-Desiree Brederson ; Ping Song ; Bin Li ; Susan M. Huang ; Heath A. McDonald ; Torben R. Neelands ; Steve P. McGaraughty ; Donna M. Gauvin ; Shailen K. Joshi ; Patricia N. Banfor ; Jason A. Segreti ; Mohamad Shebley ; Connie R. Faltynek ; Michael J. Dart ; Philip R. Kym
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4926-4947
• 全文大小：874K
• 年卷期：0
• ISSN：1520-4804

文摘

Transient receptor potential vanilloid 3 (TRPV3) is a Ca²⁺- and Na⁺-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.