Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design
Christoph W. Zapf, Richard Vargas, Marina W. H. Shen, Seungil Han, Jeanne S. Chang, Brian M. Samas, Ivan J. Samardjiev, Eddine Saiah, Frank E. Lovering, Ken Dower, Elizabeth A. Murphy, Michael D. Lowe, Seungwon Chung, Betsy S. Pierce, Lori K. Gavrin, Peter T. Symanowicz, Satwik Kamtekar, Holly H. Soutter, Arthur Lee, John D. Trzupek, Brian P. Boscoe, John P. Mathias, Katherine L. Lee, Vikram R. Rao, Iain C. Kilty, Heidi R. Hope, Joanne I. Brodfuehrer, Stephen W. Wright, Julia H. Shin, Christoph M. Dehnhardt, Richard K. Frisbie, Joseph W. Strohbach, Nikolaos Papaioannou, Susan E. Drozda, Catherine M. Ambler, Martin Hegen, David R. Anderson, Jennifer R. Thomason, Heidi M. Morgan, Andrea G. Bree, Chulho Choi, Lih-Ling Lin, Akshay Patny, Jiangli Yan, Fabien Vincent, Joel A. Goldberg, David Hepworth, Jacqueline E. Day, Kevin J. Curran
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00231

DOI: 10.1021/acs.jmedchem.7b00231

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