2. Academic Validation
  3. Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

Balancing potency, metabolic stability and permeability in pyrrolopyrimidine-based EGFR inhibitors

  • Eur J Med Chem. 2016 Nov 29:124:583-607. doi: 10.1016/j.ejmech.2016.08.068.
Jin Han 1,  Silje Henriksen 2,  Kristin G Nørsett 3,  Eirik Sundby 4,  Bård Helge Hoff 5
Affiliations

Affiliations

  • 1 Norwegian University of Science and Technology (NTNU), Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway; Norwegian University of Science and Technology (NTNU), Institute of Chemistry and Material Technology, Faculty of Technology, 7491 Trondheim, Norway. Electronic address: Jin.Han@ntnu.no.
  • 2 Norwegian University of Science and Technology (NTNU), Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Silje.Henriksen@Jotun.no.
  • 3 Norwegian University of Science and Technology (NTNU), Department of Cancer Research and Molecular Medicine, Prinsesse Kristinas gt. 1, N-7030 Trondheim, Norway. Electronic address: Kristin.Norsett@ntnu.no.
  • 4 Norwegian University of Science and Technology (NTNU), Institute of Chemistry and Material Technology, Faculty of Technology, 7491 Trondheim, Norway. Electronic address: Eirik.Sundby@hist.no.
  • 5 Norwegian University of Science and Technology (NTNU), Department of Chemistry, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Bard.Helge.Hoff@chem.ntnu.no.
PMID: 27614407 DOI: 10.1016/j.ejmech.2016.08.068
Abstract

The present study describes our continuous effort to develop epidermal growth factor receptor (EGFR) inhibitors based on the 6-aryl-pyrrolo[2,3-d]pyrimidin-4-amine scaffold. The activity-ADME space has been evaluated by synthesizing 43 new structures, including four variations of the 4-amino group and 34 different substitution patterns in the 6-aryl moiety. Most of the new pyrrolopyrimidines were highly active, with twelve analogues possessing lower IC50 values than the commercial drug Erlotinib in enzymatic assays. Ten EGFR inhibitors were also profiled in cell studies using the Ba/F3-EGFRL858R reporter cells, and all revealed nanomolar activity. However, some of the privileged structures in terms of potency had ADME short-comings: compounds containing amides, sulfonamides, amine and hydroxymethyl substituents in the 6-aryl group had low permeability and high efflux, derivatives having (R)-3-amino-3-phenylpropan-1-ol at C-4 induced hERG inhibition properties, and metabolic lability was seen for compounds having (S)-2-methoxy-1-phenylethan-1-amine at C-4. Based on a trade-off between enzymatic activity, cellular potency and ADME properties, (S)-2-phenyl-2-((6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethan-1-ol appeared as the most promising drug candidate. Cellular studies indicate this compound to have therapeutic use in EGFR driven diseases.

Keywords

ADME; EGFR; Erlotinib; Metabolism; Pyrrolopyrimidine; SAR.

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