Tuesday, August 6, 2019

Discovery of Evobrutinib: An Oral, Potent and Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases

Richard Caldwell, Hui Qiu, Ben C Askew, Andrew T Bender, Nadia Brugger, Montserrat Camps, Mohanraj Dhanabal, Vikram Dutt, Thomas Eichhorn, Anna S Gardberg, Andreas Goutopoulos, Roland Grenningloh, Jared Head, Brian Healey, Brian L Hodous, Bayard R Huck, Theresa L Johnson, Christopher Jones, Reinaldo C Jones, Igor Mochalkin, Federica Morandi, Ngan Nguyen, Michael Meyring, Justin R Potnick, Dusica Cvetinovic Santos, Ralf Schmidt, Brian Sherer, Adam Shutes, Klaus Urbahns, Ariele Viacava Follis, Ansgar A Wegener, Simone C. Zimmerli, and Lesley Liu-Bujalski

J. Med. Chem., 2019
DOI: 10.1021/acs.jmedchem.9b00794 

Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity) which preclude their evaluation in non-oncology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...