期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 2, 页码 1567-1584出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01601
关键词
-
A highly selective SGK1 inhibitor with optimized safety and pharmacokinetic profile for oral dosing has been identified as a potential disease-modifying agent for osteoarthritis.
The serine/threonine kinase SGK1 is an activator of the beta-catenin pathway and a powerful stimulator of cartilage degradation that is found to be upregulated under genomic control in diseased osteoarthritic cartilage. Today, no oral disease-modifying treatments are available and chronic treatment in this indication sets high requirements for the drug selectivity, pharmacokinetic, and safety profile. We describe the identification of a highly selective druglike 1H-pyrazolo[3,4-d]pyrimidine SGK1 inhibitor 17a that matches both safety and pharmacokinetic requirements for oral dosing. Rational compound design was facilitated by a novel hSGK1 co-crystal structure, and multiple ligand-based computer models were applied to guide the chemical optimization of the compound ADMET and selectivity profiles. Compounds were selected for subchronic proof of mechanism studies in the mouse femoral head cartilage explant model, and compound 17a emerged as a druglike SGK1 inhibitor, with a highly optimized profile suitable for oral dosing as a novel, potentially disease-modifying agent for osteoarthritis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据