Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.
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.
Wang
Haofan
H
Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Byun
Youngjoo
Y
Barinka
Cyril
C
Pullambhatla
Mrudula
M
Bhang
Hyo-Eun C
HE
Fox
James J
JJ
Lubkowski
Jacek
J
Mease
Ronnie C
RC
Pomper
Martin G
MG
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D019275:Radiopharmaceuticals; D014508:Urea; D043425:Glutamate Carboxypeptidase II; D008239:Lysine