Discovery and optimization of piperazine urea derivatives assoluble epoxide hydrolase (sEH) inhibitors


Çapan İ., Jordan P. M. , Olğaç A., Çalışkan B., Kretze C., Werz O., ...More

CHEMMEDCHEM, vol.17, pp.1-10, 2022 (Peer-Reviewed Journal)

  • Publication Type: Article / Article
  • Volume: 17
  • Publication Date: 2022
  • Doi Number: 10.1002/cmdc.202200137
  • Journal Name: CHEMMEDCHEM
  • Journal Indexes: Science Citation Index Expanded, Scopus, Agricultural & Environmental Science Database, BIOSIS, Biotechnology Research Abstracts, EMBASE, MEDLINE
  • Page Numbers: pp.1-10

Abstract

Soluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolicdiseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovereddual microsomal prostaglandin E2synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their poteSoluble epoxide hydrolase (sEH) is implicated as a potential therapeutic target for inflammation-related pathologies in the context of cardiovascular, central nervous system and metabolicdiseases. In our search for novel sEH inhibitors, we designed and synthesized novel analogs of the piperazine urea derivative 4, a previously discovereddual microsomal prostaglandin E2synthase-1 (mPGES-1)/soluble epoxide hydrolase (sEH) inhibitor, to evaluate their potential as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-on and -thion congeners (compounds 19and 20), which demonstrated selective sEH inhibition with IC50values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-on/thion functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19can be regarded as novel lead structure for further optimization of improved sEH inhibitors.ntial as sEH inhibitors. We identified two 1,3,4-oxadiazol-5-on and -thion congeners (compounds 19and 20), which demonstrated selective sEH indhibition with IC50values in the two-digit nanomolar range (42 and 56 nM, respectively). These results suggest that the installation of terminal 1,3,4-oxadiazol-5-on/thion functions to the benzyl end can be regarded as a promising secondary pharmacophore in addition to the urea group for sEH inhibition, and compound 19can be regarded as novel lead structure for further optimization of improved sEH inhibitors.