Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis.

Liver fibrosis, a consequence of chronic liver injury and a way station to cirrhosis and hepatocellular carcinoma, lacks effective treatment. Endocannabinoids acting via cannabinoid-1 receptors (CBR) induce profibrotic gene expression and promote pathologies that predispose to liver fibrosis. CBR antagonists produce opposite effects, but their therapeutic development was halted due to neuropsychiatric side effects. Inducible nitric oxide synthase (iNOS) also promotes liver fibrosis and its underlying pathologies, but iNOS inhibitors tested to date showed limited therapeutic efficacy in inflammatory diseases. Here, we introduce a peripherally restricted, orally bioavailable CBR antagonist, which accumulates in liver to release an iNOS inhibitory leaving group. In mouse models of fibrosis induced by CCl or bile duct ligation, the hybrid CBR/iNOS antagonist surpassed the antifibrotic efficacy of the CBR antagonist rimonabant or the iNOS inhibitor 1400W, without inducing anxiety-like behaviors or CBR occupancy in the CNS. The hybrid inhibitor also targeted CBR-independent, iNOS-mediated profibrotic pathways, including increased PDGF, Nlrp3/Asc3, and integrin αvβ6 signaling, as judged by its ability to inhibit these pathways in cnr1 but not in nos2 mice. Additionally, it was able to slow fibrosis progression and to attenuate established fibrosis. Thus, dual-target peripheral CBR/iNOS antagonists have therapeutic potential in liver fibrosis.