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

Autor:	Lori Krim Gavrin, David Hepworth, Jennifer R. Thomason, Iain Kilty, Joel Adam Goldberg, Christoph W. Zapf, Vikram R. Rao, Brian P. Boscoe, Akshay Patny, Peter T. Symanowicz, Marina W.H. Shen, Kevin J. Curran, Elizabeth Murphy, Martin Hegen, Fabien Vincent, Richard Vargas, Satwik Kamtekar, Heidi M. Morgan, Heidi R. Hope, Richard K. Frisbie, Jeanne S. Chang, Ken Dower, Susan E. Drozda, Strohbach Joseph Walter, Mathias John Paul, David R. Anderson, Jacqueline E. Day, Stephen W. Wright, Ivan J. Samardjiev, Seungil Han, Julia H Shin, Frank Lovering, Andrea G Bree, Arthur Lee, Holly H. Soutter, Joanne Brodfuehrer, John David Trzupek, Brian Samas, Christoph Martin Dehnhardt, Michael Dennis Lowe, Catherine M. Ambler, Seung Won Chung, Eddine Saiah, Nikolaos Papaioannou, Pierce Betsy S, Jiangli Yan, Katherine L. Lee, Lih-Ling Lin, Chulho Choi
Rok vydání:	2017
Předmět:	Models Molecular 0301 basic medicine Lactams Stereochemistry medicine.drug_class Administration Oral Carboxamide Structure-Activity Relationship 03 medical and health sciences Drug Discovery medicine Humans Structure–activity relationship Protein Kinase Inhibitors ADME Dose-Response Relationship Drug Molecular Structure biology Drug discovery Chemistry Active site Isoquinolines IRAK4 Combinatorial chemistry Interleukin-1 Receptor-Associated Kinases 030104 developmental biology Lipophilic efficiency Lipophilicity biology.protein Molecular Medicine
Zdroj:	Journal of Medicinal Chemistry. 60:5521-5542
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.7b00231
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::54d71e108dde9e50f577dacbc8e3364e https://doi.org/10.1021/acs.jmedchem.7b00231 Zobrazit plný text záznamu