4-(4-fluorophenoxy)benzaldehyde-semicarbazone and Peripheral-Nervous-System-Diseases

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

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