title: 4-Amino-pyrrolopyridine-5-carboxamide: a novel scaffold for JAK1-selective inhibitors.
abstract: 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-1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold was designed through structural modification of the potent JAK1-selective inhibitor, C2-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 µM). 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.
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University.
authors.forename: Heerim
authors.initials: H
authors.lastname: Shin
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Kim
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
mesh_terms: D066298:In Vitro Techniques; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009536:Niacinamide; D053613:Janus Kinase 1; D053614:Janus Kinase 2