Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors

被引：23

作者：

Ritzen, Andreas ^{[1
]}

Sorensen, Morten D. ^{[1
]}

Dack, Kevin N. ^{[1
]}

Greve, Daniel R. ^{[1
]}

Jerre, Anders ^{[2
]}

Carnerup, Martin A. ^{[1
]}

Rytved, Klaus A. ^{[3
]}

Bagger-Bahnsen, Jesper ^{[4
]}

机构：

[1] LEO Pharma AS, Global R&D, Drug Design, Ind Pk 55, DK-2750 Ballerup, Denmark

[2] LEO Pharma AS, Global R&D, In Vitro Biol, Ind Pk 55, DK-2750 Ballerup, Denmark

[3] LEO Pharma AS, Global R&D, Skin PK & Early Safety, Ind Pk 55, DK-2750 Ballerup, Denmark

[4] LEO Pharma AS, Global R&D, Preformulat & Early Analyt Dev, Ind Pk 55, DK-2750 Ballerup, Denmark

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 06期

关键词：

Fragments; JAK inhibitors; psoriasis; indazoles; phototoxicity; JANUS KINASE INHIBITOR; TOFACITINIB; PSORIASIS; EFFICACY; SAFETY;

D O I：

10.1021/acsmedchemlett.6b00087

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：641 / 646

页数：6

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