1817626-54-2Relevant academic research and scientific papers
Improvements to Enable the Large Scale Synthesis of 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833)
Wright, Stephen W.,Li, Bryan,Peng, Zhihui,Wei, Lulin,McInturff, Emma,Place, David,Damon, David B.,Singer, Robert A.
, p. 1835 - 1845 (2018)
An improved process for the large scale synthesis of 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (1), a candidate currently in clinical development, was developed. Key objectives were to eliminate chro
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
Lee, Katherine L.,Ambler, Catherine M.,Anderson, David R.,Boscoe, Brian P.,Bree, Andrea G.,Brodfuehrer, Joanne I.,Chang, Jeanne S.,Choi, Chulho,Chung, Seungwon,Curran, Kevin J.,Day, Jacqueline E.,Dehnhardt, Christoph M.,Dower, Ken,Drozda, Susan E.,Frisbie, Richard K.,Gavrin, Lori K.,Goldberg, Joel A.,Han, Seungil,Hegen, Martin,Hepworth, David,Hope, Heidi R.,Kamtekar, Satwik,Kilty, Iain C.,Lee, Arthur,Lin, Lih-Ling,Lovering, Frank E.,Lowe, Michael D.,Mathias, John P.,Morgan, Heidi M.,Murphy, Elizabeth A.,Papaioannou, Nikolaos,Patny, Akshay,Pierce, Betsy S.,Rao, Vikram R.,Saiah, Eddine,Samardjiev, Ivan J.,Samas, Brian M.,Shen, Marina W. H.,Shin, Julia H.,Soutter, Holly H.,Strohbach, Joseph W.,Symanowicz, Peter T.,Thomason, Jennifer R.,Trzupek, John D.,Vargas, Richard,Vincent, Fabien,Yan, Jiangli,Zapf, Christoph W.,Wright, Stephen W.
, p. 5521 - 5542 (2017/07/22)
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.
Bicyclic-Fused Heteroaryl or Aryl Compounds
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Paragraph 0831; 0855, (2015/10/28)
Compounds, tautomers and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula Ia, as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.
