Abstract
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.
MeSH terms
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Administration, Oral
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Isoquinolines / administration & dosage
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Isoquinolines / chemistry
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Isoquinolines / pharmacology*
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Lactams
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Isoquinolines
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Lactams
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Protein Kinase Inhibitors
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IRAK4 protein, human
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Interleukin-1 Receptor-Associated Kinases
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1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide