Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 9; pp. 2522 - 2526
• Main Authors: Jaime-Figueroa, Saul, De Vicente, Javier, Hermann, Johannes, Jahangir, Alam, Jin, Sue, Kuglstatter, Andreas, Lynch, Stephen M., Menke, John, Niu, Linghao, Patel, Vaishali, Shao, Ada, Soth, Michael, Vu, Minh Diem, Yee, Calvin
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2013; Elsevier
• Subjects: Binding Sites; Catalytic Domain; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Evaluation, Preclinical; ethers; JAK; JAK3; Janus kinase; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - metabolism; Kinase inhibitors; Life Sciences & Biomedicine; Molecular Docking Simulation; non-specific protein-tyrosine kinase; Pharmacology & Pharmacy; Phenyl Ethers - chemical synthesis; Phenyl Ethers - chemistry; Phenyl Ethers - metabolism; Physical Sciences; Protein Binding; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Pyridazines - chemistry; Pyrroles - chemistry; Science & Technology; Structure based drug design; Structure-Activity Relationship; Janus kinase; Kinase inhibitors; JAK; JAK3; Structure based drug design; TRIAL; CP-690,550
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.03.015

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.