Neuroscience, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium.
Bioorg Med Chem Lett. 2012 Jan 15;22(2):797-800. doi: 10.1016/j.bmcl.2011.12.068. Epub 2011 Dec 22.
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.
瞬时受体电位 A1（TRPA1）通道参与了许多炎症和痛觉过程，TRPA1 受体的拮抗剂可能为炎症或神经性疼痛、气道疾病和瘙痒等疾病提供潜在的治疗方法。在一项旨在鉴定 TRPA1 拮抗剂的高通量筛选中，4-苯基-2-硫代-1,2,3,4-四氢茚并[1,2-d]嘧啶-5-酮（1）被鉴定为一种有效的 TRPA1 受体拮抗剂。通过多组分 Biginelli 反应和随后的衍生化，已经制备了一系列类似的三环 3,4-二氢嘧啶-2-硫酮。这导致了对大鼠和人源 TRPA1 受体的效力约为 10nM 的 TRPA1 拮抗剂。活性仅存在于 4R-对映异构体中。
