Discovery of a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk.

Autor: Caldwell R; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA. Electronic address: richard.caldwell@emdserono.com., Liu-Bujalski L; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Qiu H; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Mochalkin I; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Jones R; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Neagu C; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Goutopoulos A; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Grenningloh R; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Johnson T; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Sherer B; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Gardberg A; Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA., Follis AV; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA., Morandi F; F. Hoffmann-La Roche AG, Konzern-Hauptsitz, Grenzacherstrasse 124, CH-4070 Basel, Switzerland., Head J; EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Nov 15; Vol. 28 (21), pp. 3419-3424. Date of Electronic Publication: 2018 Sep 27.
DOI: 10.1016/j.bmcl.2018.09.033
Abstrakt: Btk is an attractive target for the treatment of a range of Bcell malignancies as well as several autoimmune diseases such as murine lupus and rheumatoid arthritis. Several covalent irreversible inhibitors of Btk are currently in development including ibrutinib which was approved for treatment of B-cell malignancies. Herein, we describe our efforts using X-ray guided structure based design (SBD) to identify a novel chemical series of covalent Btk inhibitors. The resulting pyridine carboxamides were potent and selective inhibitors of Btk having excellent enzymatic and cellular inhibitory activity.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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