Open AccessBlocking Alcoholic Steatosis in Mice with a Peripherally Restricted Purine Antagonist of the Type 1 Cannabinoid Receptor
Author(s) -
George Amato,
Amruta Manke,
Danni L. Harris,
Robert W. Wiethe,
Vineetha Vasukuttan,
Rodney W. Snyder,
Timothy W. Lefever,
Ricardo A. Cortes,
Yanan Zhang,
Shaobin Wang,
Scott P. Runyon,
Rangan Maitra
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b01820
Subject(s) - cannabinoid receptor , chemistry , cannabinoid , pharmacology , endocannabinoid system , cannabinoid receptor type 2 , rimonabant , antagonist , herg , steatosis , receptor , medicine , biochemistry , potassium channel
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 2 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, 25, was found to be potent ( K i = 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 25 was tested in a mouse model of alcohol-induced liver steatosis and found to be efficacious. Taken together, 25 represents an exciting lead compound for further clinical development or refinement.