Ritzén Andreas, Sørensen Morten D, Dack Kevin N, Greve Daniel R, Jerre Anders, Carnerup Martin A, Rytved Klaus A, Bagger-Bahnsen Jesper
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.
ACS Med Chem Lett. 2016 Apr 14;7(6):641-6. doi: 10.1021/acsmedchemlett.6b00087. eCollection 2016 Jun 9.
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.
Janus激酶（JAK）抑制剂正成为治疗银屑病和其他炎症性皮肤病的新型有效药物，但其全部潜力因全身性副作用而受到阻碍。为克服这一局限性，我们着手研发用于局部应用的软药JAK抑制剂。片段筛选得到了一个吲唑命中物，通过基于结构的设计将其优化为一种强效JAK抑制剂。在6位引入一个酚基部分来扩展片段，可使活性大大提高。对酚基和磺酰胺部分的取代基进行微调，得到了一组具有类先导物性质的化合物，但发现它们具有光毒性且在光照下不稳定。
