Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1136-41. doi: 10.1016/j.bmcl.2011.11.100. Epub 2011 Dec 1.

Abstract

Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). CH5164840 displayed high oral bioavailability in mice (F=70.8%) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition=83%).

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Macrocyclic Compounds / administration & dosage
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / pharmacology*
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Macrocyclic Compounds
  • Pyrimidines