Design, synthesis, and pharmacological evaluation of 4- or 6-phenyl-pyrimidine derivatives as novel and selective Janus kinase 3 inhibitors

Abstract

As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC50 = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases.