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Blocking Alcoholic Steatosis in Mice with a Peripherally Restricted Purine Antagonist of the Type 1 Cannabinoid

George S Amato1, Amruta Manke1, Danni L Harris1

  • 1Discovery Science and Technology , RTI International , 3040 Cornwallis Road , Research Triangle Park , North Carolina 27709-2194 , United States.

Journal of Medicinal Chemistry
|April 25, 2018
PubMed

Insights

Novel peripherally restricted cannabinoid receptor 1 (CB1) antagonists show promise for treating metabolic disorders. Compound 25, a potent and selective hCB1 antagonist, effectively reduced liver steatosis in mice with minimal central nervous system effects.

Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Hepatology

Background:

  • Type 1 cannabinoid receptor (CB1) antagonists are potential treatments for obesity, liver disease, metabolic syndrome, and dyslipidemias.
  • Central nervous system (CNS) inhibition of CB1 receptors can cause adverse effects like depression and anxiety.
  • Development of peripherally restricted CB1 antagonists aims to avoid CNS-associated side effects.

Purpose of the Study:

  • To explore novel analogues of CB1 antagonists with aryl- and heteroaryl-substituted piperazine groups.
  • To identify potent and selective peripherally restricted CB1 antagonists with favorable pharmacokinetic properties.
  • To evaluate the efficacy of a lead compound in a preclinical model of liver disease.

Main Methods:

  • Synthesis and characterization of novel CB1 antagonist analogues.
  • In vitro evaluation of receptor binding affinity (Ki) and selectivity (hCB1 vs. hCB2).
  • Assessment of hERG channel liability and ADME properties (absorption, distribution, metabolism, excretion).
  • In vivo testing in a mouse model of alcohol-induced liver steatosis.

Main Results:

  • A series of mildly basic, potent antagonists of human CB1 (hCB1) were identified.
  • Compound 25 (2-chlorobenzyl piperazine) demonstrated high potency (Ki = 8 nM) and >1000-fold selectivity for hCB1 over hCB2.
  • Compound 25 exhibited no hERG liability, favorable ADME properties, and negligible CNS penetration.
  • Compound 25 was efficacious in a mouse model of alcohol-induced liver steatosis.

Conclusions:

  • Compound 25 is a potent, selective, and peripherally restricted hCB1 antagonist.
  • The favorable safety and pharmacokinetic profile of compound 25 supports its potential for clinical development.
  • Compound 25 represents a promising lead for the treatment of liver diseases and other metabolic disorders.

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