Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity.

Autor: Qiu H; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Ali Z; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Bowlan J; Repare Therapeutics, 1 Broadway, 15th Floor, Cambridge, MA, 02142, USA., Caldwell R; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Gardberg A; Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA, 02142, USA., Glaser N; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Goutopoulos A; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Head J; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Johnson T; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Maurer C; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Georgi K; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Grenningloh R; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Fang Z; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Morandi F; Cellular Enzymology, F. Hoffmann-La Roche AG, Konzern-Hauptsitz, Grenzacherstrasse 124, 4070, Basel, Switzerland., Rohdich F; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Schmidt R; Merck KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany., Follis AV; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA., Sherer B; EMD Serono Research & Development Institute, 45 A Middlesex Turnpike, Billerica, MA, 01821, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2021 Dec 14; Vol. 16 (24), pp. 3653-3662. Date of Electronic Publication: 2021 Oct 08.
DOI: 10.1002/cmdc.202100453
Abstrakt: Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors. The top molecule 1 of that series strongly inhibited CYP2C8 (IC 50 =100 nM), which was attributed to the bridged linker group. However, our effort on the linker replacement turned out to be fruitless. With the study of the X-ray crystal structure of compound 1, we envisioned the opportunity of removal of this liability via transposition of the linker moiety in 1 from C6 to C5 position of the pyridine core. With this strategy, our optimization led to the discovery of a novel series, in which the top molecule 18 A displayed reduced CYP inhibitory activity and good potency. To further explore this new series, different warheads besides acrylamide, for example cyanamide, were also tested. However, this effort didn't lead to the discovery of molecules with better potency than 18 A. The loss of potency in those molecules could be related to the reduced reactivity of the warhead or reversible binding mode. Further profiling of 18 A disclosed that it had a strong hERG (human Ether-a-go-go Related Gene) inhibition, which could be related to the phenoxyphenyl group.
(© 2021 Wiley-VCH GmbH.)
Databáze: MEDLINE
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