title: Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies.
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.
authors.affiliation: Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Haofan
authors.initials: H
authors.lastname: Wang
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.forename: Hyo-Eun C
authors.initials: HE
authors.lastname: Bhang
authors.forename: James J
authors.initials: JJ
authors.lastname: Fox
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
mesh_terms: 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
chemical_list: D019275:Radiopharmaceuticals; D014508:Urea; D043425:Glutamate Carboxypeptidase II; D008239:Lysine