Ibrutinib (Imbruvica): The First‐in‐Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia

This chapter discusses the pharmacology, structure-activity relationship (SAR), pharmacokinetics and drug metabolism, efficacy and safety, and syntheses of ibrutinib. Ibrutinib has received the approvals for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom's macroglobulinemia (WM). Ibrutinib is a selective small molecule inhibitor with subnanomolar activity against Bruton's tyrosine kinase (Btk). It reacts with Cys-481 at the rim of the ATP binding site of Btk, leading to inhibition of Btk enzymatic activity. Ibrutinib is rapidly absorbed and eliminated after oral administration, with peak plasma concentrations, mean initial half-life, and mean apparent terminal half-life of 1-2, 2-3, and 4-8 h, respectively. PCI-32765 (ibrutinib) was originally synthesized by a medicinal chemistry team through a route that is more amenable for generating analogs. Later, a more convergent route to compound 8 utilizing a telescoping synthesis has been developed to improve the synthetic efficiency.