Syntheses of conformationally constricted molecules as potential NAALADase/PSMA inhibitors

Two six-membered ring targeted analogues of PSMA inhibitors (4a and 4b) were designed on the basis of a computational analysis and synthesized. (E,Z)-Diene 10 was subjected to the nitroso Diels-Alder reaction to give the 1,4-trans six-membered ring adduct, 4a. The cis isomer 4b was derived from similar nitroso cycloaddition reactions with the corresponding (E,E)-diene and separately from cyclohexadiene. The IC50 values of 4a and 4b in a NAALADase assay were found to be 0.9 and 0.1 muM, respectively.