Guanidine Derivative ADS1017, a Potent Histamine H₃ Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H₃ and H₄ receptors (H₃R and H₄R, respectively). Moreover, we also checked their intrinsic activity toward H₃R and muscarinic M₁, M₂, and M₄ receptors (M₁R, M₂R, and M₄R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H₃ antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.