4-Amino-pyrrolopyridine-5-carboxamide: A Novel Scaffold for JAK1-Selective Inhibitors

摘要

Despite a high level of interest in selective Janus kinase 1 (JAK1) inhibitors and their potential for the treatment of inflammatory diseases such as rheumatoid arthritis (RA), only a few such inhibitors have been reported to date. In this study, a novel 4-amino-1 H -pyrrolo[2,3- b ]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C 2-methyl imidazopyrrolopyridine. Among the series studied, the 4-(2-aminoethyl)amino-pyrrolopyridine derivative, 2j , exhibited a significant 24.7-fold JAK1/JAK2 selectivity along with reasonable inhibitory activity against JAK1 (IC₅₀=2.2?μ M ). The noticeable JAK1-selectivity of 2j was then tackled through a molecular docking study, which showed that the aminoethyl functionality of 2j is well positioned to discriminate the subtle but significant difference in the size of the ligand binding sites between JAK1 and JAK2.