Phenoxyphenyl pyridines as novel state-dependent, high-potency sodium channel inhibitors.
In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Shao
Bin
B
Purdue Pharma, L.P., Discovery Research, 6 Cedar Brook Drive, Cranbury, New Jersey 08512, USA. bin.shao@pharma.com
Victory
Sam
S
Ilyin
Victor I
VI
Goehring
R Richard
RR
Sun
Qun
Q
Hogenkamp
Derk
D
Hodges
Diane D
DD
Islam
Khondaker
K
Sha
Deyou
D
Zhang
Chongwu
C
Nguyen
Phong
P
Robledo
Silvia
S
Sakellaropoulos
George
G
Carter
Richard B
RB
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015222:Sodium Channels; D013329:Structure-Activity Relationship
D000700:Analgesics; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011725:Pyridines; C568251:SCN2A protein, human; C568253:Scn2A protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels