Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.
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.
Drug 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.
Andreas
A
Ritzén
Drug 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.
Morten D
MD
Sørensen
Drug 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.
Kevin N
KN
Dack
Drug 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.
Daniel R
DR
Greve
Drug 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.
Anders
A
Jerre
Drug 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.
Martin A
MA
Carnerup
Drug 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.
Klaus A
KA
Rytved
Drug 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.
Jesper
J
Bagger-Bahnsen
Fragments; JAK inhibitors; indazoles; phototoxicity; psoriasis