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

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.