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

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.
Amarachi V Okorom 1,  Gisela Andrea Camacho-Hernandez 1,  Kristine Salomon 2,  Kuo Hao Lee 1,  Therese C Ku 1,  Jianjing Cao 1,  Sung Joon Won 1,  Jacob Friedman 1 3,  Jenny Lam 1 3,  James Paule 1 3,  Rana Rais 3,  Benjamin Klein 1,  Zheng-Xiong Xi 1,  Lei Shi 1,  Claus J Loland 2,  Amy Hauck Newman 1
Affiliations

Affiliations

  • 1 Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
  • 2 Laboratory for Membrane Protein Dynamics, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • 3 Department of Neurology, Johns Hopkins Drug Discovery, The Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
PMID: 38117239 DOI: 10.1021/acs.jmedchem.3c02037
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.

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