Lee Sunho, Kim Changhoon, Ann Jihyae, Thorat Shivaji A, Kim Eunhye, Park Jongmi, 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.
National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4383-4388. doi: 10.1016/j.bmcl.2017.08.020. Epub 2017 Aug 12.
A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with K=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.
研究了一系列2-(3-氟-4-甲基磺酰胺基苯基)丙酰胺的1-取代3-(叔丁基/三氟甲基)吡唑C区类似物对hTRPV1的拮抗作用。构效关系表明，吡唑1位的3-氯苯基是拮抗活性的最佳疏水基团，且活性对S-构型具有立体特异性，产生了K=0.1nM的超强效拮抗剂13S和16S。特别值得注意的是，13S对辣椒素和NADA具有选择性拮抗作用，而对低pH或高温则无拮抗作用。这两种化合物也被证明是rTRPV1的强效拮抗剂，在体内阻断了辣椒素的降温作用，与其体外作用机制一致。化合物13S和16S在我们的hTRPV1同源模型中的对接研究表明，它们的结合模式有所不同，13S的结合模式更类似于GRT12360的结合模式。
