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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 9; pp. 2793 - 2800
• Main Authors: 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2013; Elsevier
• Subjects: Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; 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; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; 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; Science & Technology; Structure based design; Structure-Activity Relationship; Janus kinase; Structure based design; Conformational bias; Kinase inhibitors; JAK; Kinase selectivity; RHEUMATOID-ARTHRITIS; EFFICACY; TRANSPLANT REJECTION; DISCOVERY; CP-690,550; JANUS KINASES; PSORIASIS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.02.012

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.