7KSI

Thiophenyl-Pyrazolourea Derivatives as Potent, Brian Penetrant, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors

7KSI の概要

• エントリーDOI: 10.2210/pdb7ksi/pdb
• 分子名称: Mitogen-activated protein kinase 10, 4-(4-{[(2-chloro-6-fluorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-5-methyl-N-(oxetan-3-yl)thiophene-2-carboxamide (3 entities in total)
• 機能のキーワード: jnk3, kinase inhibitor, alzheimer disease, pyrazolourea, 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: 53099.22

構造登録者

Park, H. (登録日: 2020-11-23, 公開日: 2021-03-03, 最終更新日: 2023-10-18)

主引用文献

Feng, Y.,Park, H.,Bauer, L.,Ryu, J.C.,Yoon, S.O.
Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.
Acs Med.Chem.Lett., 12:24-29, 2021

PubMed Abstract: Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor was a potent and isoform selective JNK3 inhibitor (IC = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome ( = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Moreover, cocrystal structures of compounds and in human JNK3 were solved at 1.84 Å, which showed that these JNK3 isoform selective inhibitors bound to the ATP pocket, had interactions in both hydrophobic pocket-I and hydrophobic pocket-II.

PubMed: 33488960
DOI: 10.1021/acsmedchemlett.0c00533

実験手法

X-RAY DIFFRACTION (1.726 Å)