Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies

Bioorg Med Chem Lett. 2010 Jan 1;20(1):392-7. doi: 10.1016/j.bmcl.2009.10.061. Epub 2009 Oct 24.

Abstract

We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1' site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with K(i) values below 20nM. Among them, compound 32d (K(i)=11nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1' pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / metabolism
  • Lysine / analogs & derivatives*
  • Lysine / chemical synthesis
  • Lysine / chemistry
  • Lysine / pharmacology
  • Mice
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / chemistry*
  • Structure-Activity Relationship
  • Tomography, Emission-Computed, Single-Photon
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology

Substances

  • Radiopharmaceuticals
  • Urea
  • Glutamate Carboxypeptidase II
  • Lysine