Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases.

Autor: Gerstenberger BS; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Ambler C; Pfizer Inc., Groton, Connecticut 06340, United States., Arnold EP; Pfizer Inc., Groton, Connecticut 06340, United States., Banker ME; Pfizer Inc., Groton, Connecticut 06340, United States., Brown MF; Pfizer Inc., Groton, Connecticut 06340, United States., Clark JD; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Dermenci A; Pfizer Inc., Groton, Connecticut 06340, United States., Dowty ME; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Fensome A; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Fish S; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Hayward MM; Pfizer Inc., Groton, Connecticut 06340, United States., Hegen M; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Hollingshead BD; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Knafels JD; Pfizer Inc., Groton, Connecticut 06340, United States., Lin DW; Pfizer Inc., Groton, Connecticut 06340, United States., Lin TH; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Owen DR; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Saiah E; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Sharma R; Pfizer Inc., Groton, Connecticut 06340, United States., Vajdos FF; Pfizer Inc., Groton, Connecticut 06340, United States., Xing L; Pfizer Inc., Cambridge, Massachusetts 02139, United States., Yang X; Pfizer Inc., Groton, Connecticut 06340, United States., Yang X; Pfizer Inc., Groton, Connecticut 06340, United States., Wright SW; Pfizer Inc., Groton, Connecticut 06340, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 Nov 25; Vol. 63 (22), pp. 13561-13577. Date of Electronic Publication: 2020 Aug 25.
DOI: 10.1021/acs.jmedchem.0c00948
Abstrakt: Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 ( 22 ).
Databáze: MEDLINE
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