Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors

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• 作者：Andreas Ritzén ; Morten D. Sørensen ; Kevin N. Dack ; Daniel R. Greve ; Anders Jerre ; Martin A. Carnerup ; Klaus A. Rytved ; Jesper Bagger-Bahnsen
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：7
• 期：6
• 页码：641-646
• 全文大小：454K
• 年卷期：0
• ISSN：1948-5875

文摘

Janus kinase (JAK) inhibitors are emerging as novel and efficacious drugs for treating psoriasis and other inflammatory skin disorders, but their full potential is hampered by systemic side effects. To overcome this limitation, we set out to discover soft drug JAK inhibitors for topical use. A fragment screen yielded an indazole hit that was elaborated into a potent JAK inhibitor using structure-based design. Growing the fragment by installing a phenol moiety in the 6-position afforded a greatly improved potency. Fine-tuning the substituents on the phenol and sulfonamide moieties afforded a set of compounds with lead-like properties, but they were found to be phototoxic and unstable in the presence of light.