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

• Published in: Journal of medicinal chemistry Vol. 59; no. 10; pp. 4926 - 4947
• Main Authors: Gomtsyan, Arthur, Schmidt, Robert G, Bayburt, Erol K, Gfesser, Gregory A, Voight, Eric A, Daanen, Jerome F, Schmidt, Diana L, Cowart, Marlon D, Liu, Huaqing, Altenbach, Robert J, Kort, Michael E, Clapham, Bruce, Cox, Phil B, Shrestha, Anurupa, Henry, Rodger, Whittern, David N, Reilly, Regina M, Puttfarcken, Pamela S, Brederson, Jill-Desiree, Song, Ping, Li, Bin, Huang, Susan M, McDonald, Heath A, Neelands, Torben R, McGaraughty, Steve P, Gauvin, Donna M, Joshi, Shailen K, Banfor, Patricia N, Segreti, Jason A, Shebley, Mohamad, Faltynek, Connie R, Dart, Michael J, Kym, Philip R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.05.2016; Amer Chemical Soc
• Subjects: Calcium - metabolism; Chemistry, Medicinal; Cyclobutanes - chemical synthesis; Cyclobutanes - chemistry; Cyclobutanes - pharmacology; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Life Sciences & Biomedicine; Molecular Conformation; Pharmacology & Pharmacy; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Science & Technology; Structure-Activity Relationship; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism; CATALYZED ASYMMETRIC 1,4-ADDITION; OLMSTED SYNDROME; KETONES; ACTIVATION; CHANNEL; DRUG DISCOVERY; HAIR-GROWTH; MUTATION; TRPV3; OXETANES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00287

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.