4-(4-fluorophenoxy)benzaldehyde-semicarbazone and Pain

Topics: Analgesics; Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Anticonvulsants; Benzyl Compounds; Cyclopentanes; Humans; Ion Channel Gating; Pain; Peripheral Nervous System Diseases; Pyrimidines; Semicarbazones; Sodium Channel Blockers; Sodium Channels

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.

Topics: Animals; Carbamazepine; Humans; Hyperalgesia; Lamotrigine; Male; Motor Activity; Pain; Pyrimidines; Rats; Rats, Sprague-Dawley; Semicarbazones; Sodium Channel Blockers; Tetrodotoxin; Triazines

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.

Topics: Analgesics; Animals; Cell Line; Humans; Male; Pain; Patch-Clamp Techniques; Peripheral Nervous System Diseases; Pyrazoles; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Structure-Activity Relationship

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.

Topics: Analgesics; Animals; Animals, Newborn; Brain; Cell Line; Humans; In Vitro Techniques; Male; NAV1.2 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Pain; Pain Measurement; Peripheral Nervous System Diseases; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Structure-Activity Relationship