X-ray structures of two xanthine inhibitors bound to PEPCK and N-3 modifications of substituted 1,8-dibenzylxanthines

Bioorg Med Chem Lett. 2003 Nov 3;13(21):3871-4. doi: 10.1016/s0960-894x(03)00723-6.

Abstract

The analysis of the X-ray structures of two xanthine inhibitors bound to PEPCK and a comparison to the X-ray structure of GTP bound to PEPCK are reported. The SAR at N-1, N-7 and developing SAR at C-8 are consistent with information gained from the X-ray structures of compounds 1 and 2 bound to PEPCK. Representative N-3 modifications of compound 2 that led to the discovery of 3-cyclopropylmethyl and its carboxy analogue as optimal N-3 groups are presented.

MeSH terms

  • Crystallography, X-Ray
  • Guanosine Triphosphate / metabolism
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Phosphoenolpyruvate Carboxykinase (ATP) / drug effects
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism*
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / pharmacology*

Substances

  • 1,8-dibenzylxanthine
  • Xanthines
  • Guanosine Triphosphate
  • Phosphoenolpyruvate Carboxykinase (ATP)