NIH Research Festival
FARE Award Winner
Liver fibrosis, a major contributor to liver-related mortality with lack of effective treatment. It is associated with increased activity of the CB1R system, and the CB1R antagonist rimonabant mitigates fibrosis in animal models. However, the antifibrotic efficacy is low, and neuropsychiatric side effects halted its therapeutic development. Liver fibrosis is also associated with increased activity of iNOS, and iNOS inhibitors have been shown to mitigate liver fibrosis. In order to improve the safety and antifibrotic efficacy of CB1R antagonism, we have developed highly potent, orally bioavailable hybrid CB1R antagonists that are behaviorally inactive due to low brain penetrance, and have additional activity as iNOS inhibitors. We have tested the antifibrotic efficacy of the compound in a liver fibrosis induced by bile-duct ligation (BDL). (-)-MRI1867 (CB1R antagonist/iNOS inhibitor) selectively block peripheral CB1R (Ki 2.5 nM) due to its low brain penetrance. (-)-MRI1867 directly inhibits iNOS activity in vitro by 37%, whereas rimonabant did not affect iNOS activity, when tested at 1 uM, which is below their concentration in the liver after chronic administration. Mice were subjected BDL and were treated simultaneously with equipotent daily oral doses of rimonabant (3 mg/kg), (-)-MRI1867 (3 mg/kg) or vehicle. (-)-MRI1867 was more efficacious than rimonabant in mitigating liver fibrosis. Importantly, the hybrid compound was also able to reduce fibrosis in CB1R-/- mice. Unlike rimonabant, the dual-target compound did not elicited CNS-mediated anxiogenic behavior. We conclude that dual-target CB1R/iNOS compounds can provide a novel type of pharmacotherapy for liver fibrosis with improved efficacy and safety.
Scientific Focus Area: Molecular Pharmacology
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