Leveraging Peripheral CB1 Antagonism in 1,4,5,6-Tetrahydropyridazine-Based Amidine Substituted Sulfonyl Analogs for Treating Metabolic Disorders

CB₁ receptor antagonists that are peripherally acting hold promise for treating obesity, diabetes and fibrotic disorders highlighting their importance in treating metabolic syndrome disorders (MetS). We synthesized and evaluated compounds by integrating amidine fragments into 1,4,5,6-tetrahydropyridazine-based sulfonyl urea scaffolds for blocking CB₁ receptors. Initial synthesis included compounds 10a–u, followed by expansion into distinct amidine groups (11a–18e) for detailed structure–activity relationships. The compounds displayed high CB₁R binding affinity, potent CB₁R antagonist activities and showed in vitro iNOS inhibition. Select compounds showed good oral exposure, with compound 11jE2 showing less than <13% brain penetrance, attesting to peripheral restriction. In vivo studies of four-arm antagonist 11jE2 revealed decreased food intake and body weight reduction in diet-induced obese (DIO) mice. Molecular docking and simulation analyses elucidated binding mechanisms, highlighting an unprecedented chair-boat conformation of the central core that may govern the actions in this series of compounds.