Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis.

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-β-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-β-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro.

Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors.

Here, we report the design and synthesis of pyrimidinyl heterocyclic compounds containing terminal electrophiles as irreversible covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of the structure-activity relationship utilizing kinase assays resulted in the identification of potent and selective JAK3 inhibitors such as T1, T8, T15, T22, and T29. Among them, T29 was verified as a promising JAK3 irreversible inhibitor that possessed the best bioactivity and selectivity against JAKs and kinases containing a cysteine in the residue analogous to Cys909 in JAK3, suggesting that covalent modification of this Cys residue allowed the identification of a highly selective JAK3 inhibitor.

Design and Synthesis of a Highly Selective JAK3 Inhibitor for the Treatment of Rheumatoid Arthritis.

Selective inhibition of Janus kinase 3 (JAK3) has been identified as an important strategy for the treatment of autoimmune disorders. Based on the unique cysteine 909 residue (Cys909) of JAK3 at the gatekeeper position, we have developed a new irreversible covalent inhibitor, III-4, which is highly potent and selective in targeting JAK3. Importantly, III-4 selectively inhibited JAK3 (IC  = 57 ± 1.