5WAL

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

5WAL の概要

• エントリーDOI: 10.2210/pdb5wal/pdb
• 分子名称: Non-receptor tyrosine-protein kinase TYK2, N-[2-(2,6-dichlorophenyl)-1H-imidazo[4,5-c]pyridin-4-yl]cyclopropanecarboxamide (3 entities in total)
• 機能のキーワード: tyk2, kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35095.93

構造登録者

Ultsch, M.H.,Magnuson, S. (登録日: 2017-06-26, 公開日: 2017-09-06, 最終更新日: 2023-10-04)

主引用文献

Liang, J.,Van Abbema, A.,Balazs, M.,Barrett, K.,Berezhkovsky, L.,Blair, W.S.,Chang, C.,Delarosa, D.,DeVoss, J.,Driscoll, J.,Eigenbrot, C.,Goodacre, S.,Ghilardi, N.,MacLeod, C.,Johnson, A.,Bir Kohli, P.,Lai, Y.,Lin, Z.,Mantik, P.,Menghrajani, K.,Nguyen, H.,Peng, I.,Sambrone, A.,Shia, S.,Smith, J.,Sohn, S.,Tsui, V.,Ultsch, M.,Williams, K.,Wu, L.C.,Yang, W.,Zhang, B.,Magnuson, S.
Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.
Bioorg. Med. Chem. Lett., 27:4370-4376, 2017

PubMed Abstract: Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.

PubMed: 28830649
DOI: 10.1016/j.bmcl.2017.08.022

実験手法

X-RAY DIFFRACTION (2.45 Å)