Synthesis and SAR of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers.
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.
Knutsen
Lars J S
LJ
Ionix Pharmaceuticals Ltd, 418 Cambridge Science Park, Milton Road, Cambridge CB4 0PA, UK. LKnutsen@cephalon.com
Hobbs
Christopher J
CJ
Earnshaw
Christopher G
CG
Fiumana
Andrea
A
Gilbert
Jenny
J
Mellor
Sarah L
SL
Radford
Fleur
F
Smith
Nichola J
NJ
Birch
Philip J
PJ
Russell Burley
J
J
Ward
Stuart D C
SD
James
Iain F
IF
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*
D000700:Analgesics; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D007202:Indicators and Reagents; D045162:Thiazolidinediones