2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Jul 13;60(13):5521-5542. doi: 10.1021/acs.jmedchem.7b00231.
Katherine L Lee,  Catherine M Ambler,  David R Anderson,  Brian P Boscoe,  Andrea G Bree,  Joanne I Brodfuehrer,  Jeanne S Chang,  Chulho Choi,  Seungwon Chung,  Kevin J Curran,  Jacqueline E Day,  Christoph M Dehnhardt,  Ken Dower,  Susan E Drozda,  Richard K Frisbie,  Lori K Gavrin,  Joel A Goldberg,  Seungil Han,  Martin Hegen,  David Hepworth,  Heidi R Hope,  Satwik Kamtekar,  Iain C Kilty,  Arthur Lee,  Lih-Ling Lin,  Frank E Lovering,  Michael D Lowe,  John P Mathias,  Heidi M Morgan 1,  Elizabeth A Murphy,  Nikolaos Papaioannou,  Akshay Patny,  Betsy S Pierce,  Vikram R Rao,  Eddine Saiah,  Ivan J Samardjiev,  Brian M Samas,  Marina W H Shen,  Julia H Shin,  Holly H Soutter,  Joseph W Strohbach,  Peter T Symanowicz,  Jennifer R Thomason,  John D Trzupek,  Richard Vargas,  Fabien Vincent,  Jiangli Yan 1,  Christoph W Zapf,  Stephen W Wright
Affiliations

Affiliation

  • 1 Worldwide Medicinal Chemistry, Pfizer Inc. , 1070 Science Center Drive, San Diego, California 92121, United States.
PMID: 28498658 DOI: 10.1021/acs.jmedchem.7b00231
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.

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