New structure–activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO

Jun Li, Michael L. Schulte, Michael L. Nickels, H. Charles Manning

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine.

Original languageEnglish
Pages (from-to)3472-3477
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number15
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • Cancer
  • Precision medicine
  • Pyrazolopyrimidine
  • SAR
  • TSPO

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