title: Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists.
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.
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gfesser
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Voight
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Schmidt
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Bruce
authors.initials: B
authors.lastname: Clapham
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Phil B
authors.initials: PB
authors.lastname: Cox
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Anurupa
authors.initials: A
authors.lastname: Shrestha
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Rodger
authors.initials: R
authors.lastname: Henry
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: David N
authors.initials: DN
authors.lastname: Whittern
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Puttfarcken
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jill-Desiree
authors.initials: JD
authors.lastname: Brederson
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Torben R
authors.initials: TR
authors.lastname: Neelands
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Steve P
authors.initials: SP
authors.lastname: McGaraughty
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Banfor
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Shebley
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dart
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: D002118:Calcium / Q000378:metabolism; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000619432:3-(hydroxy(pyridin-2-yl)methyl)-1-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)cyclobutanol; D003503:Cyclobutanes; D011725:Pyridines; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; D002118:Calcium