Design, synthesis and biological evaluation of 7 H -pyrrolo[2,3- d ]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis

摘要

Abstract Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7 H -pyrrolo [2,3- d ]pyrimidin-4-amine scaffold that potently inhibited Btk in?vitro . Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16 . B16 preferentially inhibited Btk (IC 50 ?=?21.70?±?0.82?nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto -phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1?cell lines with IC 50 values over 30?μM. Moreover, B16 showed very weak potential to block the hERG channel (IC 50 ?=?11.10?μM) in comparison to ibrutinib (IC 50 ?=?0.97?μM). Owing to its favorable physicochemical properties (ClogP?=?2.53, aqueous solubility?≈?0.1?mg/mL), pharmacokinetic profiles (F?=?49.15%, t 1/2 ?=?7.02?h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis. Graphical abstract Display Omitted Highlights ? A series of novel compounds bearing 7 H -pyrrolo [2,3- d ]pyrimidin-4-amine scaffold have been synthesized and identified as potent Btk inhibitors. ? Compound B16 significantly inhibited Btk (IC 50 ?=?21.70?±?0.82?nM) with moderate kinase selectivity. ? B16 showed weaker inhibition to hERG channel (IC 50 ?=?11.10?μM) than ibrutinib (IC 50 ?=?0.97?μM). ? Owing to its favorable physicochemical properties (ClogP?=?2.53, aqueous solubility?≈?0.1?mg/ml) and pharmacokinetic profiles (F?=?49.15%, t 1/2 ?=?7.02h), B16 exhibited slightly better anti-arthritis efficacy than ibrutinib in CIA mice.