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.