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J Med Chem ; 67(2): 1225-1242, 2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38228402

RESUMEN

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.


Asunto(s)
Ensayos Analíticos de Alto Rendimiento , Indazoles , Quinasas Asociadas a Receptores de Interleucina-1 , Piridinas , Animales , Humanos , Sitios de Unión , Inflamación
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