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

Autor: Caldwell RD; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Qiu H; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Askew BC; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Bender AT; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Brugger N; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Camps M; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Dhanabal M; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Dutt V; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Eichhorn T; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Gardberg AS; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Goutopoulos A; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Grenningloh R; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Head J; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Healey B; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Hodous BL; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Huck BR; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Johnson TL; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Jones C; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Jones RC; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Mochalkin I; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Morandi F; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Nguyen N; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Meyring M; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Potnick JR; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Santos DC; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Schmidt R; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Sherer B; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Shutes A; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Urbahns K; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Follis AV; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Wegener AA; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Zimmerli SC; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States., Liu-Bujalski L; EMD Serono Research & Development Institute, Inc. (a Business of Merck KGaA, Darmstadt, Germany) , 45 A Middlesex Turnpike , Billerica , Massachusetts 01821 , United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2019 Sep 12; Vol. 62 (17), pp. 7643-7655. Date of Electronic Publication: 2019 Aug 15.
DOI: 10.1021/acs.jmedchem.9b00794
Abstrakt: 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 nononcology 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.
Databáze: MEDLINE