title: The design and synthesis of novel, phosphonate-containing transient receptor potential melastatin 8 (TRPM8) antagonists.
abstract: A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.
authors.affiliation: Janssen Pharmaceuticals, Spring House, PA 19477-0776, United States. jmatthew@its.jnj.com
authors.forename: Jay M
authors.initials: JM
authors.lastname: Matthews
authors.forename: Ning
authors.initials: N
authors.lastname: Qin
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Colburn
authors.forename: Scott L
authors.initials: SL
authors.lastname: Dax
authors.forename: Mike
authors.initials: M
authors.lastname: Hawkins
authors.forename: James J
authors.initials: JJ
authors.lastname: McNally
authors.forename: Laura
authors.initials: L
authors.lastname: Reany
authors.forename: Mark A
authors.initials: MA
authors.lastname: Youngman
authors.forename: Judith
authors.initials: J
authors.lastname: Baker
authors.forename: Tasha
authors.initials: T
authors.lastname: Hutchinson
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Lubin
authors.forename: Michael
authors.initials: M
authors.lastname: Neeper
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brandt
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Stone
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
mesh_terms: D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D015195:Drug Design; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D063065:Organophosphonates; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human