Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis

We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at Cannabinoid Receptor type 1 (CB₁R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB₁ receptor (CB₁R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB₁R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB₁R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB₁Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB₁R antagonism.