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

Abstract

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine Hand Hreceptors (HR and HR, respectively). Moreover, we also checked their intrinsic activity toward HR and muscarinic M, M, and Mreceptors (MR, MR, and MR, respectively). Since ADS1017 has been proved to be the most selective and highly potent Hantagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of itsefficacy, 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.