Discovery of 5-Aryl-2,4-diaminopyrimidine Compounds as Potent and Selective IRAK4 Inhibitors.
| Autor: | Chen Y; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States., Singh R; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States., Lin N; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States., Taylor V; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States., Masuda ES; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States., Payan DG; Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Apr 04; Vol. 13 (4), pp. 714-719. Date of Electronic Publication: 2022 Apr 04 (Print Publication: 2022). |
| DOI: | 10.1021/acsmedchemlett.2c00056 |
| Abstrakt: | IRAK4 kinase plays a key role in TLR/IL-1R signaling pathways that regulate innate immune responses, and if uncontrolled, it is responsible for various inflammatory disorders. By high-throughput screening (HTS) and hit-to-lead optimization, compounds with a 5-aryl-2,4-diaminopyrimidine core structure have been identified as potent IRAK4 inhibitors. A cocrystal structure of IRAK4 protein with an early lead molecule helped with understanding the structure-activity relationship and the design of the new compounds. Initial HTS hits from this series of compounds were also found to inhibit TAK1 kinase, which would cause liver toxicity and potentially bone marrow failure. Optimization of this series resulted in improved selectivity over TAK1 kinase. The TAK1 selectivity was found to be closely associated with different sizes and types of substituents at the 5-position of the pyrimidine. The impact of other pyrimidine substituents on the potency and selectivity was also explored. A few representative compounds were evaluated in IL-1β-induced IL-6 inhibition animal model studies and showed modest efficacy. Competing Interests: The authors declare no competing financial interest. (© 2022 American Chemical Society.) |
| Databáze: | MEDLINE |
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