Journal of Medicinal Chemistry p. 5521 - 5542 (2017)
Update date:2022-08-15
Topics:
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.
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.
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