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Discovery of Selective Inhibitors of NaV1.7 Templated on Saxitoxin as Therapeutics for Pain
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-10-18 , DOI: 10.1021/acsmedchemlett.2c00378
Hassan Pajouhesh 1 , Anton Delwig 1 , Jacob T Beckley 2 , Sheri Klas 2 , Dennis Monteleone 1 , Xiang Zhou 1 , George Luu 1 , J Du Bois 3 , John C Hunter 1 , John V Mulcahy 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-10-18 , DOI: 10.1021/acsmedchemlett.2c00378
Hassan Pajouhesh 1 , Anton Delwig 1 , Jacob T Beckley 2 , Sheri Klas 2 , Dennis Monteleone 1 , Xiang Zhou 1 , George Luu 1 , J Du Bois 3 , John C Hunter 1 , John V Mulcahy 1
Affiliation
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The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of NaV1.7. Most inhibitors of NaV1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate NaV1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.
中文翻译：
发现以石房蛤毒素为模板的 NaV1.7 选择性抑制剂作为疼痛治疗药物
电压门控钠通道亚型 Na V 1.7 作为治疗疼痛的非阿片类研究新药的靶标引起了广泛的兴趣。对在外周运动神经元、中枢神经系统、骨骼肌和心脏中表达的同源、脱靶钠通道亚型的选择性，对 Na V 1.7 小分子抑制剂的开发提出了重大挑战。迄今为止公开的大多数Na V 1.7抑制剂属于优先结合通道失活构象的一类芳基和酰基磺酰胺。通过利用通道细胞外孔中灵长类 Na V 1.7 特有的序列变异，天然产物石房蛤毒素的一系列双胍类似物已被鉴定出，它们对通道的静息构象具有有效作用。一种感兴趣的化合物25 比脱靶钠通道亚型表现出 >600 倍的选择性，并且在急性疼痛的临床前模型中有效。
更新日期：2022-10-18
中文翻译：
发现以石房蛤毒素为模板的 NaV1.7 选择性抑制剂作为疼痛治疗药物
电压门控钠通道亚型 Na V 1.7 作为治疗疼痛的非阿片类研究新药的靶标引起了广泛的兴趣。对在外周运动神经元、中枢神经系统、骨骼肌和心脏中表达的同源、脱靶钠通道亚型的选择性，对 Na V 1.7 小分子抑制剂的开发提出了重大挑战。迄今为止公开的大多数Na V 1.7抑制剂属于优先结合通道失活构象的一类芳基和酰基磺酰胺。通过利用通道细胞外孔中灵长类 Na V 1.7 特有的序列变异，天然产物石房蛤毒素的一系列双胍类似物已被鉴定出，它们对通道的静息构象具有有效作用。一种感兴趣的化合物25 比脱靶钠通道亚型表现出 >600 倍的选择性，并且在急性疼痛的临床前模型中有效。
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