1 research outputs found
Discovery of Clinical Candidate 1‑{[(2<i>S</i>,3<i>S</i>,4<i>S</i>)‑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
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 <b>40</b>). This compound displays a 5-unit
increase in lipophilic efficiency from the fragment hit, excellent
kinase selectivity, and pharmacokinetic properties suitable for oral
administration