Blocking Alcoholic
Steatosis in Mice with a Peripherally
Restricted Purine Antagonist of the Type 1 Cannabinoid Receptor
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Abstract
Type
1 cannabinoid receptor (CB1) antagonists have demonstrated
promise for the treatment of obesity, liver disease, metabolic syndrome,
and dyslipidemias. However, the inhibition of CB1 receptors in the
central nervous system can produce adverse effects, including depression,
anxiety, and suicidal ideation. Efforts are now underway to produce
peripherally restricted CB1 antagonists to circumvent CNS-associated
undesirable effects. In this study, a series of analogues were explored
in which the 4-aminopiperidine group of compound <b>2</b> was
replaced with aryl- and heteroaryl-substituted piperazine groups both
with and without a spacer. This resulted in mildly basic, potent antagonists
of human CB1 (hCB1). The 2-chlorobenzyl piperazine, <b>25</b>, was found to be potent (<i>K</i><sub>i</sub> = 8 nM);
to be >1000-fold selective for hCB1 over hCB2; to have no hERG liability; and to possess favorable ADME properties including high oral absorption and negligible CNS penetration. Compound <b>25</b> was tested
in a mouse model of alcohol-induced liver steatosis and found to be
efficacious. Taken together, <b>25</b> represents an exciting
lead compound for further clinical development or refinement