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The development of an SAR with small molecule inhibitors of prostate specific membrane antigen (PSMA)

¹ Molecular Insight Pharmaceuticals, Cambridge, Massachusetts

1236

Objectives: Synthesize and evaluate novel glutamate-urea (Glu-urea-X) heterodimers to develop a structure activity relationship (SAR) for small molecule inhibitors of PSMA as radiotracers for the detection of prostate cancer.

Methods: The Glu-Urea-Lys moiety was employed as a building block for the synthesis of a series of Glu-urea-X heterodimers where X = -N-(o-I, m-I, p-I, , p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and -(p-I, p-Br, p-Cl, H)-phenyl ureido-Lys. The compounds were prepared by reaction of the free amine of the protected Glu-urea-Lys intermediate with the appropriate phenylisocyanates or via reductive alkylation with the desired substituted benzaldehyde derivatives. The affinities were determined by screening in a competitive binding assay.

Results: Overall synthetic yields ranged from 20-60%. The benzyl lysine series showed a clear relationship between the nature of the halogen substituent and PSMA binding affinity. In the para substituted series the IC50 values followed the trend Cl >I = Br > >F = H. In addition, the binding affinity was influenced by the position of the halogen atom on the aryl ring (IC50 values p-I > o-I>> m-I). The nature of the halogen atom had little effect on the binding affinity in the para substituted phenylureido-Lys series (IC50 values Cl = I = Br = F = H).

Conclusions: An SAR was established for two series of Glu-urea-X heterodimers by systematically substituting halogen atoms on the aryl ring. These data have led to the development of clinical candidates for the detection of prostate cancer.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maresca, K. Articles by Babich, J. PubMed Articles by Maresca, K. Articles by Babich, J.