Substituted biaryl oxazoles, imidazoles, and thiazoles as sodium channel blockers

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 18; pp. 5536 - 5540
• Main Authors: Tyagarajan, Sriram, Chakravarty, Prasun K., Zhou, Bishan, Fisher, Michael H., Wyvratt, Mathew J., Lyons, Kathy, Klatt, Tracy, Li, Xiaohua, Kumar, Sanjeev, Williams, Brande, Felix, John, Priest, Birgit T., Brochu, Richard M., Warren, Vivien, Smith, McHardy, Garcia, Maria, Kaczorowski, Gregory J., Martin, William J., Abbadie, Catherine, McGowan, Erin, Jochnowitz, Nina, Parsons, William H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2010; Elsevier
• Subjects: Analgesics; Animals; Biaryl imidazoles; Biaryl oxazoles; Biaryl thiazoles; Biological and medical sciences; Dogs; Humans; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; Imidazoles - therapeutic use; Medical sciences; Microsomes, Liver - metabolism; Na v1.7 blockers; NAV1.7 Voltage-Gated Sodium Channel; Neuralgia - drug therapy; Neuropathic pain; Neuropathy; Neuropharmacology; Oxazoles - chemistry; Oxazoles - metabolism; Oxazoles - pharmacology; Oxazoles - therapeutic use; Pharmacology. Drug treatments; Rats; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - metabolism; Sodium Channel Blockers - pharmacology; Sodium Channel Blockers - therapeutic use; Sodium Channels - metabolism; Thiazoles - chemistry; Thiazoles - metabolism; Thiazoles - pharmacology; Thiazoles - therapeutic use; Voltage-gated sodium channel; Biaryl oxazoles; Biaryl imidazoles; Na v1.7 blockers; Biaryl thiazoles; Neuropathic pain; Voltage-gated sodium channel; Imidazole derivatives; Five membered ring; Rat; Nitrogen heterocycle; Thiazole derivatives; 1.7 blockers; Na; Structure activity relation; Chemical synthesis; Oxazole derivatives; Oxygen nitrogen heterocycle; Sulfur nitrogen heterocycle; Voltage-gated canal; Rodentia; Oral administration; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Analgesic; Biphenyl derivatives; Animal; Carboxamide; Fluorine Organic compounds; Sodium channel blocker; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.07.064

A series of low molecular weight biaryl substituted oxazoles, imidazoles, and thiazoles were identified as Na v1.7 blockers. These state dependent sodium channel blockers were synthesized and evaluated for treatment of neuropathic pain. Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.