7S1N

N-Aromatic-Substituted Indazole Derivatives as Brain Penetrant and Orally Bioavailable JNK3 Inhibitors

7S1N の概要

• エントリーDOI: 10.2210/pdb7s1n/pdb
• 分子名称: Mitogen-activated protein kinase 10, 4-[5-(2-chloro-6-fluoroanilino)-6-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl]-N-(oxetan-3-yl)thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: mapk10, jnk3, kinase inhibitor, alzheimers diseases, indazole, azaindazole, neurodegeneration, transferase, transferase-inhibitor complex, 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: 53107.24

構造登録者

Park, H. (登録日: 2021-09-02, 公開日: 2021-11-03, 最終更新日: 2023-10-18)

主引用文献

Feng, Y.,Park, H.,Ryu, J.C.,Yoon, S.O.
N -Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors.
Acs Med.Chem.Lett., 12:1546-1552, 2021

PubMed Abstract: An indazole/aza-indazole scaffold was developed as a novel chemotype for JNK3 inhibition. Extensive structure activity relationship (SAR) studies utilizing various in vitro and in vivo assays led to potent and highly selective JNK3 inhibitors with good oral bioavailability and high brain penetration. One lead compound, , was a potent and selective JNK3 inhibitor (IC = 0.005 μM) that had significant inhibition (>80% at 1 μM) to only JNK3 and JNK2 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in the human liver microsome ( = 92 min), and was orally bioavailable and brain penetrant (brain/plasma ratio: 56%). The cocrystal structure of in human JNK3 at a 2.1 Å resolution showed that indazole or aza-indazole-based JNK3 inhibitors demonstrated a type I kinase inhibition/binding.

PubMed: 34676036
DOI: 10.1021/acsmedchemlett.1c00334

実験手法

X-RAY DIFFRACTION (2.11 Å)