Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.
Basic Information
ID: ALA4477220
Journal: ACS Med Chem Lett
Title: Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.
Authors: Ritzén A, Sørensen MD, Dack KN, Greve DR, Jerre A, Carnerup MA, Rytved KA, Bagger-Bahnsen J.
Abstract: 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.
CiteXplore: 27326341
DOI: 10.1021/acsmedchemlett.6b00087
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