Structure-activity relationship of N-methyl-N-aralkyl-peptidylamines as novel N-type calcium channel blockers.
Selective N-type voltage sensitive calcium channel (VSCC) blockers have shown efficacy in several animal models of stroke and pain. In the process of searching for small molecule N-type calcium channel blockers, we have identified a series of N-methyl-N-aralkyl-peptidylamines with potent functional activity at N-type VSCCs. The most active compound discovered in this series is PD 173212 (11, IC50 = 36 nM in the IMR-32 assays). SAR and pharmacological evaluation of this series are described.
Hu
L Y
LY
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Ryder
T R
TR
Rafferty
M F
MF
Dooley
D J
DJ
Geer
J J
JJ
Lotarski
S M
SM
Miljanich
G P
GP
Millerman
E
E
Rock
D M
DM
Stoehr
S J
SJ
Szoke
B G
BG
Taylor
C P
CP
Vartanian
M G
MG
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004151:Dipeptides; C121650:PD 173212