Optimization of Pyrimidine Compounds as Potent JAK1 Inhibitors and the Discovery of R507 as a Clinical Candidate.

Autor: Chen Y; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Li H; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Yen R; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Heckrodt TJ; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., McMurtrie D; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Singh R; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Taylor V; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Masuda ES; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Park G; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States., Payan DG; Rigel Pharmaceuticals Inc., South San Francisco, California 94080, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Oct 25; Vol. 13 (11), pp. 1805-1811. Date of Electronic Publication: 2022 Oct 25 (Print Publication: 2022).
DOI: 10.1021/acsmedchemlett.2c00411
Abstrakt: Janus kinases (JAK) play a critical role in JAK/signal transducer and activator of transcription (STAT) signaling pathways that mediate immune response and cell growth. From high-throughput screening (HTS) hit to lead optimization, a series of pyrimidine compounds has been discovered as potent JAK1 inhibitors with selectivity over JAK2. Cell-based assays were used as primary screening methods for evaluating potency and selectivity, the results were further assessed and confirmed by biochemical and additional cellular assays for lead molecules. Also discussed is the unique correlation between a trifluomethyl group and CYP3A4 inhibition in the presence of NADPH, the activity of which was successfully decreased with the reduction of fluoro-atoms, increasing IC 50 from 0.5 μM to >10 μM. The development of novel and scalable synthetic routes for amino-phenyl intermediates was essential for the discovery of late-stage lead molecules, including clinical candidate R507 ( 33 ). In preclinical studies, 33 exhibited great efficacy in mouse studies by inhibiting IFNγ expression induced by IL-2 and in a rat collagen-induced arthritis disease model.
Competing Interests: The authors declare no competing financial interest.
(© 2022 American Chemical Society.)
Databáze: MEDLINE
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