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t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
- t-Butyl pyridine and phenyl C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists
- Lee, Sunho; Kang, Dong Wook; Ryu, HyungChul; Kim, Changhoon; Ann, Jihyae; Lee, Hobin; Kim, Eunhye; Hong, Sunhye; Choi, Sun; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeewoo
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- 0968-0896; 1464-3391
- vol. 25, no. 8, pp. 2451 - 2462
- Vanilloid receptor 1; TRPV1 antagonists; Analgesic
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- A series of 2-substituted 6-t-butylpyridine and 4-t-butylphenyl C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis of structure activity relationships indicated that the pyridine derivatives generally exhibited a little better antagonism than did the corresponding phenyl surrogates for most of the series. Among the compounds, compound 7 showed excellent antagonism toward capsaicin activation with K-i = 0.1 nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10 mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the AFB-regions of 7S with Tyr511 and the interactions between the t-butyl and ethyl groups in the C-region of 7S with the two hydrophobic binding pockets of hTRPV1 contributed to the high potency. (C) 2017 Elsevier Ltd. All rights reserved.
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