1263285-61-5Relevant articles and documents
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)
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.
Synthesis of chiral pyrrolidine derivatives from (S)-pyroglutamic acid. II. 4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-ones and 5,S-disubstituted 2-pyrrolidinones
Nagasaka, Tatsuo,Imai, Tomoko
, p. 36 - 42 (2007/10/03)
The chiral pyrrolidine derivatives, 4-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-2-ones (10 and 11) and 5,5-disubstituted 2- pyrrolidinones (20, 21 and 22), were synthesized starting from (S)- pyroglutamic acid and absolute configuration determination was made based on the 1H-NMR spectra of the bicyclic lactam intermediates.
