Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors
Andreas Ritzén1, Morten D Sørensen1, Kevin N Dack1
1Drug Design, In Vitro Biology, Skin PK and Early Safety, and Preformulation & Early Analytical Development, Global R&D, LEO Pharma A/S , Industriparken 55, DK-2750 Ballerup, Denmark.
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.
Related Concept Videos
Drug Discovery: Overview
Inhibitors of Bacterial DNA Synthesis
Five-Membered Heterocyclic Aromatic Compounds: Overview
Dipeptidyl Peptidase 4 Inhibitors
Inhibitors of Bacterial Protein Synthesis
Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...


