Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.
Wang, H., Byun, Y., Barinka, C., Pullambhatla, M., Bhang, H.E., Fox, J.J., Lubkowski, J., Mease, R.C., Pomper, M.G.(2010) Bioorg Med Chem Lett 20: 392-397
- PubMed: 19897367 
- DOI: https://doi.org/10.1016/j.bmcl.2009.10.061
- Primary Citation of Related Structures:  
3IWW - PubMed 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.
Organizational Affiliation: 
Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.