Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome

…, J DeVicente, JC Hermann, S Jaime-Figueroa…

文献索引：Lynch, Stephen M.; Devicente, Javier; Hermann, Johannes C.; Jaime-Figueroa, Saul; Jin, Sue; Kuglstatter, Andreas; Li, Hongju; Lovey, Allen; Menke, John; Niu, Linghao; Patel, Vaishali; Roy, Douglas; Soth, Michael; Steiner, Sandra; Tivitmahaisoon, Parcharee; Vu, Minh Diem; Yee, Calvin Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 9 p. 2793 - 2800

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被引用次数: 13

摘要

Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and ...