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.
Purdue Pharma, L.P., Discovery Research, 6 Cedar Brook Drive, Cranbury, New Jersey 08512, USA. bin.shao@pharma.com
Bin
B
Shao
Sam
S
Victory
Victor I
VI
Ilyin
R Richard
RR
Goehring
Qun
Q
Sun
Derk
D
Hogenkamp
Diane D
DD
Hodges
Khondaker
K
Islam
Deyou
D
Sha
Chongwu
C
Zhang
Phong
P
Nguyen
Silvia
S
Robledo
George
G
Sakellaropoulos
Richard B
RB
Carter
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