2-Methylacrylamide as a bioisoster of thiourea group for 1, 3-dibenzylthioureido TRPV1 receptor antagonists. Issue 11 (15th June 2018)

• Record Type: Journal Article
• Authors: Park, Seol Rin; Kim, Juhyun; Lee, Sun Young; Park, Young-Ho; Kim, Hee-Doo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 11(2018)
• Page Start: 2080
• Page End: 2083
• Publication Date: 2018-06-15
• Subjects: 2-Methylacrylamide -- Bioisoster -- TRPV1 -- 1, 3-Dibenzylthioureas -- Antagonist -- 45Ca2+-Influx assay; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.04.044
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 1, 3-Dibenzylthioureas having methanesulfonylamide are potent TRPV1 antagonists. Thiourea moiety of 1, 3-dibenzylthioureas could be replaced to 2-methylacrylamide. This replacement enable us to design the more druggable TRPV1 related antagonists. Abstract: 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 45 Ca 2+ -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. Compound7c, 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog7e having vinyl moiety showed the most potent activity with 0.022 μM of IC50 value, indicating that thiourea group of 1, 3-dibenzylthioureas could be replaced to 2-methylacrylamide without loss of their potencies.