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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2793-2800
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites Conformational bias Crystallography, X-Ray Drug Design Hydrophobic and Hydrophilic Interactions Indazoles - chemistry JAK Janus kinase Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - metabolism Janus Kinase 2 - antagonists & inhibitors Janus Kinase 2 - metabolism Janus Kinase 3 - antagonists & inhibitors Janus Kinase 3 - metabolism Kinase inhibitors Kinase selectivity Molecular Docking Simulation Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Structure, Tertiary Pyrazines - chemical synthesis Pyrazines - chemistry Pyrazines - metabolism Structure based design Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	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 improved selectivity within the JAK family.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.02.012