3-(4-phenoxyphenyl)pyrazoles: a novel class of sodium channel blockers.
A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophilic (+pi) electronegative (+sigma) substituents at the ortho and/or para position. Substitution at the pyrazole nitrogen with a H-bond donor improves potency. Compound 18 showed robust activity in the rat Chung neuropathy paradigm.
Discovery Research, Purdue Pharma L.P., 6 Cedar Brook Drive, Cranbury, New Jersey 08512, Novartis. ji.yang@pharma.com
Ji
J
Yang
Parviz
P
Gharagozloo
Jiangchao
J
Yao
Victor I
VI
Ilyin
Richard B
RB
Carter
Phong
P
Nguyen
Silvia
S
Robledo
Richard M
RM
Woodward
Derk J
DJ
Hogenkamp
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D008297:Male; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D018408:Patch-Clamp Techniques; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C483900:3-(4-(4-nitrophenoxy)phenyl)-1H-pyrazole-1-carboxamide; D000700:Analgesics; D011720:Pyrazoles; D026941:Sodium Channel Blockers