新型氮杂苯并呋喃TRPA1拮抗剂作为体内工具的开发。
Development of novel azabenzofuran TRPA1 antagonists as in vivo tools.
作者信息
Copeland Katrina W, Boezio Alessandro A, Cheung Eugene, Lee Josie, Olivieri Philip, Schenkel Laurie B, Wan Qian, Wang Weiya, Wells Mary C, Youngblood Beth, Gavva Narender R, Lehto Sonya G, Geuns-Meyer Stephanie
机构信息
Department of Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
Department of Pharmaceutics, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
出版信息
Bioorg Med Chem Lett. 2014 Aug 1;24(15):3464-8. doi: 10.1016/j.bmcl.2014.05.069. Epub 2014 Jun 6.
The transient receptor potential ankyrin 1 (TRPA1) channel is activated by noxious stimuli including chemical irritants and endogenous inflammatory mediators. Antagonists of this channel are currently being investigated for use as therapeutic agents for treating pain, airway disorders, and itch. A novel azabenzofuran series was developed that demonstrated in vitro inhibition of allyl isothiocyanate (AITC)-induced (45)Ca(2+) uptake with nanomolar potencies against both human and rat TRPA1. From this series, compound 10 demonstrated in vivo target coverage in an AITC-induced flinching model in rats while providing unbound plasma concentrations up to 16-fold higher than the TRPA1 rat IC50.
瞬时受体电位锚蛋白1（TRPA1）通道可被包括化学刺激物和内源性炎症介质在内的有害刺激激活。目前正在研究该通道的拮抗剂作为治疗疼痛、气道疾病和瘙痒的治疗药物。已开发出一种新型氮杂苯并呋喃系列化合物，该系列化合物在体外对烯丙基异硫氰酸酯（AITC）诱导的（45）Ca（2+）摄取具有抑制作用，对人和大鼠TRPA1的抑制效力均为纳摩尔级别。在该系列化合物中，化合物10在大鼠AITC诱导的退缩模型中显示出体内靶点覆盖，同时其未结合血浆浓度比TRPA1大鼠IC50高16倍。
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