Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: a potent, broad-spectrum state-dependent sodium channel blocker for treating pain states.
Voltage-gated Na(+) channels may play important roles in establishing pathological neuronal hyperexcitability associated with chronic pain in humans. Na(+) channel blockers, such as carbamazepine (CBZ) and lamotrigine (LTG), are efficacious in treating neuropathic pain; however, their therapeutic utility is compromised by central nervous system side effects. We reasoned that it may be possible to gain superior control over pain states and, in particular, a better therapeutic index, by designing broad-spectrum Na(+) channel blockers with higher potency, faster onset kinetics, and greater levels of state dependence than existing drugs. 2-[4-(4-Chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide (PPPA) is a novel structural analog of the state-dependent Na(+) channel blocker V102862 [4-(4-fluorophenoxy)benzaldehyde semicarbazone]. Tested on recombinant rat Na(v)1.2 channels and native Na(+) currents in cultured rat dorsal root ganglion neurons, PPPA was approximately 1000 times more potent, had 2000-fold faster binding kinetics, and > or =10-fold higher levels of state dependence than CBZ and LTG. Tested in rat pain models against mechanical endpoints, PPPA had minimal effective doses of 1 to 3 mg/kg p.o. in partial sciatic nerve ligation, Freund's complete adjuvant, and postincisional pain. In all cases, efficacy was similar to clinically relevant comparators. Importantly, PPPA did not produce motor deficits in the accelerating Rotarod assay of ataxia at doses up to 30 mg/kg p.o., indicating a therapeutic index >10, which was superior to CBZ and LTG. Our experiments suggest that high-potency, broad-spectrum, state-dependent Na(+) channel blockers will have clinical utility for treating neuropathic, inflammatory, and postsurgical pain. Optimizing the biophysical parameters of broad-spectrum voltage-gated Na(+) channel blockers may lead to improved pain therapeutics.
Ilyin
Victor I
VI
Discovery Research, Purdue Pharma LP, Cranbury, NJ 08512, USA. victor.ilyin@pharma.com
Pomonis
James D
JD
Whiteside
Garth T
GT
Harrison
James E
JE
Pearson
Michelle S
MS
Mark
Lilly
L
Turchin
Paul I
PI
Gottshall
Susan
S
Carter
Richard B
RB
Nguyen
Phong
P
Hogenkamp
Derk J
DJ
Olanrewaju
Shakira
S
Benjamin
Elfrida
E
Woodward
Richard M
RM
D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D000077213:Lamotrigine; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012664:Semicarbazones / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology
C514016:2-(4-(4-chloro-2-fluorophenoxy)phenyl)pyrimidine-4-carboxamide; D011743:Pyrimidines; D012664:Semicarbazones; D026941:Sodium Channel Blockers; D014227:Triazines; C119606:4-(4-fluorophenoxy)benzaldehyde semicarbazone; D002220:Carbamazepine; D013779:Tetrodotoxin; D000077213:Lamotrigine