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J Med Chem. 2018 Feb 8;61(3):1130-1152. doi: 10.1021/acs.jmedchem.7b01598. Epub 2018 Jan 23.

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.

Author information

1
Medicine Design, Pfizer Inc , 1 Portland Street, Cambridge, Massachusetts 02139, United States.
2
Medicine Design, Pfizer Inc , Eastern Point Road, Groton, Connecticut 06340, United States.
3
Veterinary Medicine Research and Development, Pfizer Inc , 333 Portage Street, Kalamazoo, Michigan 49007, United States.
4
Medicinal Chemistry, Pfizer Inc , 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, United States.
5
Chemical Research Development, Pfizer Inc , Eastern Point Road, Groton, Connecticut 06340, United States.
6
Medicine Design, Pfizer Inc , 1 Burtt Road, Andover, Massachusetts 01810, United States.
7
Inflammation and Immunology, Pfizer Inc , 1 Portland Street, Cambridge, Massachusetts 02139, United States.

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.

PMID:
29298069
DOI:
10.1021/acs.jmedchem.7b01598
[Indexed for MEDLINE]

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