Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Furthermore, optimization o...

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Veröffentlicht in:Journal of medicinal chemistry 2016-12, Vol.60 (2)
Hauptverfasser: Jones, Peter, Storer, R. Ian, Sabnis, Yogesh A., Wakenhut, Florian M., Whitlock, Gavin A., England, Katherine S., Mukaiyama, Takasuke, Dehnhardt, Christoph M., Coe, Jotham W., Kortum, Steve W., Chrencik, Jill E., Brown, David G., Jones, Rhys M., Murphy, John R., Yeoh, Thean, Morgan, Paul, Kilty, Iain
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Sprache:eng
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60 APPLIED LIFE SCIENCES
amides
assays
hydrocarbons
inhibition
peptides and proteins
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Zusammenfassung:By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Furthermore, optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.
ISSN:0022-2623