2-Methylacrylamide as a bioisoster of thiourea group for 1,3-dibenzylthioureido TRPV1 receptor antagonists |
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Authors: | Seol Rin Park Juhyun Kim Sun Young Lee Young-Ho Park Hee-Doo Kim |
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Institution: | 1. College of Pharmacy, Sookmyung Women’s University, Seoul 04310, South Korea;2. AmorePacific R & D Center, Youngin-Si, Gyeonggi-do 17014, South Korea |
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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 45Ca2+-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 IC50 value, indicating that thiourea group of 1,3-dibenzylthioureas could be replaced to 2-methylacrylamide without loss of their potencies. |
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Keywords: | 2-Methylacrylamide Bioisoster TRPV1 1 3-Dibenzylthioureas Antagonist Corresponding author |
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