Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

被引：6

作者：

Nilsson, Magnus ^{[1
]}

Berggren, Kristina ^{[1
]}

Berglund, Susanne ^{[1
]}

Cerboni, Silvia ^{[2
]}

Collins, Mia ^{[2
]}

Dahl, Goran ^{[3
]}

Elmqvist, David ^{[4
]}

Grimster, Neil P. ^{[5
]}

Hendrickx, Ramon ^{[6
]}

Johansson, Johan R. ^{[1
]}

Kettle, Jason G. ^{[5
]}

Lepisto, Matti ^{[1
]}

Rhedin, Magdalena ^{[2
]}

Smailagic, Amir ^{[2
]}

Su, Qibin ^{[5
]}

Wennberg, Tiiu ^{[2
]}

Wu, Allan ^{[7
]}

Osterlund, Torben ^{[8
]}

Naessens, Thomas ^{[2
]}

Mitra, Suman ^{[2
]}

机构：

[1] AstraZeneca, BioPharmaceut R&D, Resp & Immunol, Med Chem Res & Early Dev, SE-43183 Gothenburg, Sweden

[2] AstraZeneca, BioPharmaceut R&D, Resp & Immunol, Biosci Res & Early Dev, SE-43183 Gothenburg, Sweden

[3] AstraZeneca, BioPharmaceut R&D, Struct & Biophys Res & Early Dev, Discovery Sci, SE-43183 Gothenburg, Sweden

[4] AstraZeneca, BioPharmaceut R&D, Pharmaceut Sci, Early Prod Dev, SE-43183 Gothenburg, Sweden

[5] AstraZeneca R&D, Oncol R&D, Waltham, MA 02451 USA

[6] AstraZeneca, BioPharmaceut R&D, Res & Early Dev, Resp & Immunol,DMPK, SE-43183 Gothenburg, Sweden

[7] AstraZeneca R&D, Discovery Sci, R&D, Waltham, MA 02451 USA

[8] AstraZeneca, BioPharmaceut R&D, Res & Early Dev, Discovery Sci,Mechanist Biol & Profiling, SE-43183 Gothenburg, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年

关键词：

T-CELLS; TISSUE DISTRIBUTION; JAK1; INHIBITORS; IMMUNITY; IDENTIFICATION; MECHANISMS;

D O I：

10.1021/acs.jmedchem.3c00554

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.

引用

页码：13400 / 13415

页数：16

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