Terrett Jack A, Chen Huifen, Shore Daniel G, Villemure Elisia, Larouche-Gauthier Robin, Déry Martin, Beaumier Francis, Constantineau-Forget Léa, Grand-Maître Chantal, Lépissier Luce, Ciblat Stéphane, Sturino Claudio, Chen Yong, Hu Baihua, Lu Aijun, Wang Yunli, Cridland Andrew P, Ward Stuart I, Hackos David H, Reese Rebecca M, Shields Shannon D, Chen Jun, Balestrini Alessia, Riol-Blanco Lorena, Lee Wyne P, Liu John, Suto Eric, Wu Xiumin, Zhang Juan, Ly Justin Q, La Hank, Johnson Kevin, Baumgardner Matt, Chou Kang-Jye, Rohou Alexis, Rougé Lionel, Safina Brian S, Magnuson Steven, Volgraf Matthew
Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Paraza Pharma, Inc. 2525 Avenue Marie-Curie, Montreal, Quebec H4S 2E1, Canada.
J Med Chem. 2021 Apr 8;64(7):3843-3869. doi: 10.1021/acs.jmedchem.0c02023. Epub 2021 Mar 22.
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong target engagement in a rat AITC-induced pain assay, compound was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound was determined via cryogenic electron microscopy to a resolution of 3 Å, revealing the binding site and mechanism of action for this class of antagonists.
瞬时受体电位锚蛋白1（TRPA1）是一种非选择性的钙通透性离子通道，在初级感觉神经元中高度表达，作为外源性和内源性刺激的多模式传感器发挥作用，并且由于其与神经性疼痛和呼吸系统疾病的关联，作为一种抑制靶点引起了广泛关注。在此，我们描述了一系列强效、选择性和口服生物可利用的TRPA1小分子拮抗剂的优化过程，从而发现了一种新型的基于四氢呋喃的连接子。鉴于在大鼠异硫氰酸烯丙酯诱导的疼痛试验中理化性质的平衡和强大的靶点结合能力，化合物 进入了豚鼠卵清蛋白哮喘模型，在该模型中它表现出显著的剂量依赖性炎症反应降低。此外，通过低温电子显微镜确定了与化合物 结合的TRPA1通道的结构，分辨率为3 Å，揭示了这类拮抗剂的结合位点和作用机制。
