title: Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers.
abstract: A series of new N-type (Ca(v)2.2) calcium channel blockers derived from the 'hit' structures 2-(3-bromo-4-fluorophenyl)-3-(2-pyridin-2-ylethyl)thiazolidin-4-one 9 and its 2-[4-(4-bromophenyl)pyridin-3-yl]-3-isobutyl analogue 10 is described. Extensive SAR studies using a range of synthetic approaches resulted in novel, patented compounds with IC50 values of up to 0.2 microM in an in vitro IMR32 assay, and selectivities for N/L of up to 30-fold. The new compounds described have potential in treatment of neuropathic pain.
authors.affiliation: Ionix Pharmaceuticals Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PA, UK. LKnutsen@cephalon.com
authors.forename: Lars J S
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hobbs
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Earnshaw
authors.forename: Andrea
authors.initials: A
authors.lastname: Fiumana
authors.forename: Jenny
authors.initials: J
authors.lastname: Gilbert
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mellor
authors.forename: Fleur
authors.initials: F
authors.lastname: Radford
authors.forename: Nichola J
authors.initials: NJ
authors.lastname: Smith
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Birch
authors.forename: J
authors.initials: J
authors.lastname: Russell Burley
authors.forename: Stuart D C
authors.initials: SD
authors.lastname: Ward
authors.forename: Iain F
authors.initials: IF
authors.lastname: James
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007202:Indicators and Reagents; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D007202:Indicators and Reagents; D045162:Thiazolidinediones