一系列吲唑类TRPA1拮抗剂的发现。
Discovery of a Series of Indazole TRPA1 Antagonists.
作者信息
Pryde David C, Marron Brian E, West Christopher W, Reister Steven, Amato George, Yoger Katrina, Antonio Brett, Padilla Karen, Cox Peter J, Turner Jamie, Warmus Joseph S, Swain Nigel A, Omoto Kiyoyuki, Mahoney John H, Gerlach Aaron C
机构信息
Pfizer Worldwide Medicinal Chemistry, Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridgeshire CB21 6GS, U.K.
Pfizer Neuroscience and Pain Research Unit, 4222 Emperor Boulevard, Suite 350, Durham, North Carolina NC27703, United States.
出版信息
ACS Med Chem Lett. 2017 May 18;8(6):666-671. doi: 10.1021/acsmedchemlett.7b00140. eCollection 2017 Jun 8.
Abstract
A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and DMPK profiles are discussed. Good exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds.
摘要
描述了一系列TRPA1拮抗剂，其核心结构为吲唑部分。讨论了其物理性质和药物代谢动力学特征。几种类似物具有良好的暴露量，从而能够在炎性疼痛的啮齿动物模型中评估其疗效。两种化合物在全身或局部给药时在这些模型中显示出显著活性。构建了蛋白质嵌合体以表明该系列化合物结合在通道的S5区域，并使用计算对接模型提出示例化合物的结合模式。
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