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Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.

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.

SUBMITTER: Ritzen A

PROVIDER: S-EPMC4904270 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.

Ritzén Andreas A Sørensen Morten D MD Dack Kevin N KN Greve Daniel R DR Jerre Anders A Carnerup Martin A MA Rytved Klaus A KA Bagger-Bahnsen Jesper J

ACS medicinal chemistry letters 20160414 6

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 ...[more]

PMID: 27326341

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