Exploration of 3-aminoazetidines as triple reuptake inhibitors by bioisosteric modification of 3-α-Oxyazetidine

Minsoo Han, Chiman Song, Nakcheol Jeong, Hoh Gyu Hahn

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies.

Original languageEnglish
Pages (from-to)999-1004
Number of pages6
JournalACS Medicinal Chemistry Letters
Issue number9
Publication statusPublished - 2014 Sept 11

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.


  • 3-aminoazetidines
  • Depression
  • bioisosterism
  • triple reuptake inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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