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  • Title: Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.
    Author: Qiu H, Ali Z, Bender A, Caldwell R, Chen YY, Fang Z, Gardberg A, Glaser N, Goettsche A, Goutopoulos A, Grenningloh R, Hanschke B, Head J, Johnson T, Jones C, Jones R, Kulkarni S, Maurer C, Morandi F, Neagu C, Poetzsch S, Potnick J, Schmidt R, Roe K, Viacava Follis A, Wing C, Zhu X, Sherer B.
    Journal: Bioorg Med Chem; 2021 Jun 15; 40():116163. PubMed ID: 33932711.
    Abstract:
    Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.
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