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Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.

Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.

Authors :
Vazquez ML
Kaila N
Strohbach JW
Trzupek JD
Brown MF
Flanagan ME
Mitton-Fry MJ
Johnson TA
TenBrink RE
Arnold EP
Basak A
Heasley SE
Kwon S
Langille J
Parikh MD
Griffin SH
Casavant JM
Duclos BA
Fenwick AE
Harris TM
Han S
Caspers N
Dowty ME
Yang X
Banker ME
Hegen M
Symanowicz PT
Li L
Wang L
Lin TH
Jussif J
Clark JD
Telliez JB
Robinson RP
Unwalla R
Source :
Journal of medicinal chemistry [J Med Chem] 2018 Feb 08; Vol. 61 (3), pp. 1130-1152. Date of Electronic Publication: 2018 Jan 23.
Publication Year :
2018

Abstract

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Details

Language :
English
ISSN :
1520-4804
Volume :
61
Issue :
3
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
29298069
Full Text :
https://doi.org/10.1021/acs.jmedchem.7b01598