Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.

Autor: Chen Y; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States. Electronic address: ychen@rigel.com., Tso K; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Heckrodt TJ; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Li H; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Yen R; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Lin N; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Singh R; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Taylor V; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Masuda ES; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Park G; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States., Payan DG; Rigel Pharmaceuticals Inc, 1180 Veterans Boulevard, South San Francisco, CA 94080, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Oct 01; Vol. 73, pp. 128900. Date of Electronic Publication: 2022 Jul 18.
DOI: 10.1016/j.bmcl.2022.128900
Abstrakt: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1β induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies.
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Databáze: MEDLINE
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