Design and synthesis of alkyl substituted pyridino[2,3-D]pyrimidine compounds as PI3Kα/mTOR dual inhibitors with improved pharmacokinetic properties and potent in vivo antitumor activity

Bioorg Med Chem. 2018 Aug 7;26(14):3992-4000. doi: 10.1016/j.bmc.2018.06.025. Epub 2018 Jun 18.

Abstract

Using pyridino[2,3-D]pyrimidine as the core, total 13 pyridino[2,3-D]pyrimidine derivatives with different alkyl substituents at C2 site have been designed and synthesized to search for novel PI3Kα/mTOR dual inhibitors. Most of the target compounds showed potent mTOR inhibition activity with IC50 values ranging from single to double digit nanomole. Five target compounds exhibited pronounced PI3Kα inhibition activity. In vitro cellular assay indicated that most of the target compounds showed excellent antiproliferative activity, especially 3j whose potency against SKOV3 was 8-fold higher than the positive control AZD8055. In vitro metabolic stability study found that 3j had a comparable stability to that of AZD8055. More importantly, 3j showed better antitumor activity and pharmacokinetic properties in vivo as compared with AZD8055.

Keywords: Antitumor activity; PI3Kα/mTOR dual inhibitors; Pyridino[2,3-D]pyrimidine compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • MTOR protein, human
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • TOR Serine-Threonine Kinases