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

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 IC50 from 0.5 mu M to >10 mu M. 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 IFN gamma expression induced by IL-2 and in a rat collagen-induced arthritis disease model.

Automated summary

This study discovered a series of potent JAK1 inhibitors with selectivity over JAK2 and discussed the unique correlation between a trifluoromethyl group and CYP3A4 inhibition. Cell-based assays and biochemical and additional cellular assays were used to evaluate the potency and selectivity of the lead molecules, and novel synthetic routes were developed for the discovery of late-stage lead molecules.