1. Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors
- Author
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Sidney Pitt, Sylwia Stachura, Rosemary Zhang, Steven G. Nadler, Kim W. McIntyre, Hong Wu, James Kempson, Jonathan Lippy, John Hynes, Joel C. Barrish, Zhonghui Lu, Percy H. Carter, Gary L. Schieven, Bin Jiang, Kate Gillooly, William J. Pitts, Javed Khan, Stephen T. Wrobleski, Jingwu Duan, Aberra Fura, Guoxiang Shen, John S. Tokarski, John S. Sack, and Luisa Salter-Cid
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Molecular Conformation ,Pharmaceutical Science ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Catalytic Domain ,Drug Discovery ,Mice, Inbred BALB C ,biology ,Chemistry ,Translation (biology) ,Pyridazines ,Tyrosine kinase 2 ,Molecular Medicine ,Half-Life ,hERG ,Molecular Dynamics Simulation ,Pyrrolopyridazine ,Cell Line ,03 medical and health sciences ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,In vivo ,Potency ,Animals ,Humans ,Pyrroles ,Molecular Biology ,Protein Kinase Inhibitors ,Inflammation ,TYK2 Kinase ,Binding Sites ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Janus Kinase 3 ,Janus Kinase 1 ,Janus Kinase 2 ,0104 chemical sciences ,Rats ,Disease Models, Animal ,030104 developmental biology ,Murine model ,biology.protein - Abstract
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
- Published
- 2017