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

J Med Chem. 2024 Jan 11;67(1):709-727. doi: 10.1021/acs.jmedchem.3c02037. Epub 2023 Dec 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / pharmacology
  • Animals
  • Central Nervous System Stimulants* / pharmacology
  • Cocaine*
  • Dopamine Plasma Membrane Transport Proteins
  • Mice
  • Piperidines / pharmacology
  • Rats
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Amines
  • Serotonin Plasma Membrane Transport Proteins
  • Cocaine
  • Central Nervous System Stimulants
  • Piperidines