Modifications to 1-(4-(2-Bis(4-fluorophenyl)methyl)sulfinyl)alkyl Alicyclic Amines That Improve Metabolic Stability and Retain an Atypical DAT Inhibitor Profile

Research output: Contribution to journalJournal articleResearchpeer-review

  • Amarachi V. Okorom
  • Gisela Andrea Camacho-Hernandez
  • Salomon, Kristine Walløe
  • Kuo Hao Lee
  • Therese C. Ku
  • Jianjing Cao
  • Sung Joon Won
  • Jacob Friedman
  • Jenny Lam
  • James Paule
  • Rana Rais
  • Benjamin Klein
  • Zheng Xiong Xi
  • Lei Shi
  • Løland, Claus Juul
  • Amy Hauck Newman

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in the preclinical models of psychostimulant use disorders (PSUD). In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol (JJC8-091, 3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. Improvements in DAT affinity and metabolic stability were desirable for discovering pipeline drug candidates. Thus, a series of 1-(4-(2-bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines were synthesized and evaluated for binding affinities at DAT and the serotonin transporter (SERT). Replacement of the piperazine with either a homopiperazine or a piperidine ring system was well tolerated at DAT (Ki range = 3-382 nM). However, only the piperidine analogues (20a-d) showed improved metabolic stability in rat liver microsomes as compared to the previously reported analogues. Compounds 12b and 20a appeared to retain an atypical DAT inhibitor profile, based on negligible locomotor activity in mice and molecular modeling that predicts binding to an inward-facing conformation of DAT.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number1
Pages (from-to)709-727
Number of pages19
Publication statusPublished - 2024

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