title: Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors.
abstract: We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity.
authors.affiliation: Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, 340 Kingsland Street, Nutley, NJ 07110-1199, USA. saul.jaime@roche.com
authors.forename: Saul
authors.initials: S
authors.lastname: Jaime-Figueroa
authors.forename: Javier
authors.initials: J
authors.lastname: De Vicente
authors.forename: Johannes
authors.initials: J
authors.lastname: Hermann
authors.forename: Alam
authors.initials: A
authors.lastname: Jahangir
authors.forename: Sue
authors.initials: S
authors.lastname: Jin
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lynch
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.forename: Linghao
authors.initials: L
authors.lastname: Niu
authors.forename: Vaishali
authors.initials: V
authors.lastname: Patel
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.forename: Michael
authors.initials: M
authors.lastname: Soth
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.forename: Calvin
authors.initials: C
authors.lastname: Yee
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004353:Drug Evaluation, Preclinical; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D010647:Phenyl Ethers; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; D053616:Janus Kinase 3