A Peripherally Selective CB1 Receptor Inverse Agonist Improves Metabolic Syndrome in Mice

Abstract

The type 1 cannabinoid receptor (CB1) can be targeted to treat major diseases like type 2 diabetes, fibrosis and steatohepatitis. This has led to the development and profiling of several CB1 antagonists; one such drug being rimonabant, a CNS penetrating inverse agonist, for the treatment of obesity. However, rimonabant was discontinued due to CNS‐related adverse psychiatric effects in a subset of patients. Accumulating evidence indicates that peripheral blockade of CB1 with antagonists that have limited brain penetration is an attractive strategy to treat various disorders. Our research has identified RTI‐1092663, a peripherally selective purine‐based inverse agonist with limited brain penetration (~1% of plasma concentration) and good ADME properties, as a therapeutic agent for the treatment of metabolic syndrome. C57/BL6J male mice were fed a standard chow or high fat diet (60% fat calories) from 6 – 24 weeks and were administered vehicle or RTI‐1092663 at doses of 0.1, 0.3 or 1.0mg/kg, PO/day from weeks 20–24. Oral glucose tolerance test was performed 3 days prior to euthanasia. High fat diet (HFD) significantly increased body weight, liver weights and blood glucose levels in both fasted and fed states. HFD also increased hepatic mRNA expression of CXCR1. Treatment with RTI‐1092663 resulted in a significant decline in body weight and liver weight. Further, RTI‐1092663 treatment lowered fasting glucose levels and demonstrated a dose dependent improvement in glucose tolerance. This compound also inhibited increased neutrophil infiltration as demonstrated by a significant decline in CXCR1 mRNA expression. These data suggest that compound RTI‐1092663 could be further developed for the treatment of metabolic syndrome and other diseases.Support or Funding Information1R01AA023256‐011R01DK100414‐01A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.