Journal of Medicinal Chemistry p. 241 - 259 (2020)
Update date:2022-08-17
Topics:
Meijer, Femke A.
Doveston, Richard G.
De Vries, Rens M.J.M.
Vos, Ga?l M.
Vos, Alex A.A.
Leysen, Seppe
Scheepstra, Marcel
Ottmann, Christian
Milroy, Lech-Gustav
Brunsveld, Luc
Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 (FM26), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt.
View MoreContact:86-25-51817806
Address:No. 216, middle longpan road, jincheng tower, floor 21-22, nanjing ,china
Xi'an HO-SHINE Bio-Technology Co., Ltd
Contact:+86 (29) 8248-5435/18292020086
Address:No.6 Shiyuan Road Xian City Shaanxi Province, 710048 China
Dayang Chem (Hangzhou) Co.,Ltd.
website:http://www.dycnchem.com
Contact:+86-571-88938639
Address:9/F, Unit 2 Changdi Torch Building, 259# WenSan Road, Xihu District, Hangzhou City 310012, P.R.China
SHENYANG COMEBOARD TECHNOLOGY CO., LTD
Contact:+86-24-25724626
Address:Room2210,Tianbao International Building,No.8-1 Weigong South Street,Tiexi District,Shenyang,China
Changzhou Jiana Chemical Co.,Ltd
website:http://www.jianachem.com
Contact:86-0519-88731808
Address:Zhenglu Town Wujin City, Jiangsu Province
Doi:10.1016/S0022-2860(03)00342-9
(2003)Doi:10.1080/10426500307777
(2003)Doi:10.1021/acs.joc.9b03168
(2020)Doi:10.1007/s11172-021-3188-1
(2021)Doi:10.1016/j.tetlet.2008.08.112
(2008)Doi:10.1002/cmdc.201402373
(2015)