Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists.
J Med Chem, 2016/05/26;59(10):4926-47.
Gomtsyan A[1], Schmidt RG[1], Bayburt EK[1], Gfesser GA[1], Voight EA[1], Daanen JF[1], Schmidt DL[1], Cowart MD[1], Liu H[1], Altenbach RJ[1], Kort ME[1], Clapham B[1], Cox PB[1], Shrestha A[1], Henry R[1], Whittern DN[1], Reilly RM[1], Puttfarcken PS[1], Brederson JD[1], Song P[1], Li B[1], Huang SM[1], McDonald HA[1], Neelands TR[1], McGaraughty SP[1], Gauvin DM[1], Joshi SK[1], Banfor PN[1], Segreti JA[1], Shebley M[1], Faltynek CR[1], Dart MJ[1], Kym PR[1]
Affiliations
PMID: 27077528DOI: 10.1021/acs.jmedchem.6b00287
Impact factor: 8.039
Abstract
Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- 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.
MeSH terms
Calcium; Cyclobutanes; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Conformation; Pyridines; Structure-Activity Relationship; TRPV Cation Channels
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