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
Laboratory of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Deagu, Gyeongsan-si, Gyeongsangbuk-do 38430, Republic of Korea.
Bioorg Med Chem. 2017 Apr 15;25(8):2451-2462. doi: 10.1016/j.bmc.2017.03.004. Epub 2017 Mar 6.
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=0.1nM and compound 60S demonstrated a strong antiallodynic effect with 83% MPE at 10mg/kg in the neuropathic pain model. The docking study of 7S in our hTRPV1 homology model indicated that the interactions between the A/B-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.
研究了一系列2-取代的6-叔丁基吡啶和2-(3-氟-4-甲基磺酰胺基苯基)丙酰胺的4-叔丁基苯基C区域类似物对hTRPV1的拮抗作用。构效关系分析表明，在该系列的大多数化合物中，吡啶衍生物的拮抗作用通常比相应的苯基替代物略好。在这些化合物中，化合物7对辣椒素激活表现出优异的拮抗作用，K = 0.1 nM，化合物60S在神经性疼痛模型中，10 mg/kg时显示出83% 的最大可能效应（MPE）的强效抗痛觉过敏作用。7S在我们的hTRPV1同源模型中的对接研究表明，7S的A/B区域与Tyr511之间的相互作用以及7S的C区域中的叔丁基和乙基与hTRPV1的两个疏水结合口袋之间的相互作用导致了高效能。
