Synthesis and biological evaluation of disubstituted pyrimidines as selective 5-HT2C agonists

Juhyeon Kim, Yoon Jung Kim, Ashwini M. Londhe, Ae Nim Pae, Hyunah Choo, Hak Joong Kim, Sun Joon Min

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT2C agonists. To improve selectivity for 5-HT2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT2C selective agonist.

Original languageEnglish
Article number3234
JournalMolecules
Volume24
Issue number18
DOIs
Publication statusPublished - 2019 Sept 5

Bibliographical note

Funding Information:
This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C).

Funding Information:
Acknowledgments: This work was financially supported by the Korea Health Industry Development Institute (KHIDI, HI16C1677, HI17C1037), the National Research Foundation of Korea (NRF-2019R1A2C1008186) and the research fund of Hanyang University (HY-2015-N). Binding affinity data were generously provided by the US National Institute of Mental Health (NIMH) Psychoactive Drug Screening Program (HHSN-271-2008-00025-C).

Publisher Copyright:
© 2019 by the authors.

Keywords

  • 5-HT receptor
  • Binding affinity
  • Cell-based assay
  • Disubstituted pyrimidine
  • Selectivity

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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