Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722)

J Med Chem. 2018 Sep 27;61(18):8226-8240. doi: 10.1021/acs.jmedchem.8b00690. Epub 2018 Sep 10.

Abstract

Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Clinical Trials, Phase I as Topic
  • Drug Discovery*
  • Female
  • Humans
  • Male
  • Methylation
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism*
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tissue Distribution
  • Triazoles / chemistry*
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*

Substances

  • BOS172722
  • Cell Cycle Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Triazoles
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • TTK protein, human