Discovery of IRAK4 Inhibitors BAY1834845 (Zabedosertib) and BAY1830839 .

Autor: Bothe U; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Günther J; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Nubbemeyer R; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Siebeneicher H; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Ring S; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Bömer U; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Peters M; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Rausch A; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Denner K; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Himmel H; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Sutter A; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Terebesi I; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Lange M; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Wengner AM; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Guimond N; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Thaler T; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Platzek J; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Eberspächer U; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Schäfer M; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Steuber H; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Zollner TM; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Steinmeyer A; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany., Schmidt N; Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Jan 25; Vol. 67 (2), pp. 1225-1242. Date of Electronic Publication: 2024 Jan 16.
DOI: 10.1021/acs.jmedchem.3c01714
Abstrakt: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839 , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.
Databáze: MEDLINE
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