Park Seol Rin, Kim Juhyun, Lee Sun Young, Park Young-Ho, Kim Hee-Doo
College of Pharmacy, Sookmyung Women's University, Seoul 04310, South Korea.
AmorePacific R & D Center, Youngin-Si, Gyeonggi-do 17014, South Korea.
Bioorg Med Chem Lett. 2018 Jun 15;28(11):2080-2083. doi: 10.1016/j.bmcl.2018.04.044. Epub 2018 Apr 17.
In order to replace thiourea group with the more drug-like moiety for 1,3-dibenzylthioureas having TRPV1 antagonist activity, we introduced a set of functional groups between the two aromatic rings based on bioisosteric replacement. The synthesized bioisosteres of 1,3-dibenzylthioureas were tested for their antagonist activities on TRPV1 by Ca-influx assay using neonatal rat cultured spinal sensory neurons. Among the tested 14 kinds of bioisosters, 2-methylacrylamide group was the best candidate to replace thiourea group. Compound 7c, 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog 7e having vinyl moiety showed the most potent activity with 0.022 μM of IC value, indicating that thiourea group of 1,3-dibenzylthioureas could be replaced to 2-methylacrylamide without loss of their potencies.
为了用更具药物样性质的基团取代具有TRPV1拮抗剂活性的1,3 - 二苄基硫脲中的硫脲基团，我们基于生物电子等排体替换在两个芳环之间引入了一组官能团。使用新生大鼠培养的脊髓感觉神经元，通过钙内流测定法测试了合成的1,3 - 二苄基硫脲生物电子等排体对TRPV1的拮抗剂活性。在测试的14种生物电子等排体中，2 - 甲基丙烯酰胺基团是取代硫脲基团的最佳候选者。化合物7c，即ATC - 120的2 - 甲基丙烯酰胺类似物，其拮抗剂活性与ATC - 120相当。此外，具有乙烯基部分的2 - 甲基丙烯酰胺类似物7e表现出最有效的活性，IC值为0.022μM，这表明1,3 - 二苄基硫脲的硫脲基团可以被2 - 甲基丙烯酰胺取代而不损失其效力。
