Synthesis and in vitro evaluation of piperazinyl-ureido sulfamates as steroid sulfatase inhibitors

Research output: Contribution to journalArticlepeer-review

Authors

  • Davide Moi
  • Lucy Rimmer
  • Alisha Jaffri
  • Alessandro Deplano
  • Gianfranco Balboni
  • Valentina Onnis
  • Barry V L Potter

Colleges, School and Institutes

External organisations

  • University of Birmingham

Abstract

Two new piperazinyl-ureido single ring aryl sulfamate-based inhibitor series were designed against the emerging oncology drug target steroid sulfatase (STS), for which there are existing potent steroidal and non-steroidal agents in clinical trials. 4-(Piperazinocarbonyl)aminosulfamates (5–31) were obtained by reacting 4-hydroxyarylamines with phenylchloroformate, subsequent sulfamoylation of the resulting hydroxyarylcarbamates and coupling of the product with 1-substituted piperazines. Pyrimidinyl-piperazinourea sulfamates (35–42) were synthesized by pyrimidine ring closure of 4-Boc-piperazine-1-carboxamidine with 3-(dimethylamino)propenones, deprotection and coupling with the sulfamoylated building block. Target ureidosulfamates 5–31 and 35–42 were evaluated both as STS inhibitors in vitro using a lysate of JEG-3 human placenta choriocarcinoma cell line and in a whole cell assay. SAR conclusions were drawn from both series. In series 35–42 the best inhibitory activity is related to the presence of a benzofuryl on the pyrimidine ring. In series 5–31 the best inhibitory activity was shown by the ureas bearing 4-chlorophenyl, 3,4-dichlorophenyl groups or aliphatic chains at the piperazino 4-nitrogen displaying IC50 in the 33–94 nM concentration range. Final optimization to the low nanomolar level was achieved through substitution of the arylsulfamate ring with halogens. Four halogenated arylsulfamates of high potency were achieved and two of these 19 and 20 had IC50 values of 5.1 and 8.8 nM respectively and are attractive for potential in vivo evaluation and further development. We demonstrate the optimization of this new series to low nanomolar potency, employing fluorine substitution, providing potent membrane permeant inhibitors with further development potential indicating piperazinyl-ureido aryl sulfamate derivatives as an attractive new class of STS inhibitors.

Details

Original languageEnglish
Article number111614
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume182
Early online date12 Aug 2019
Publication statusPublished - 15 Nov 2019

Keywords

  • piperazines, ureido compounds, sulfamates, pyrimidines, steroid sulfatase, enzyme inhibition