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
  • 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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