AI Article Synopsis
- The study focused on designing and synthesizing pyridazine-3-carboxamides that selectively activate the CB2 receptor, utilizing scaffold hopping and bioisosterism techniques.
- The compounds were tested for activity using calcium mobilization assays, with more than half showing moderate to potent CB2 agonist effects; six exhibited EC values under 35 nM.
- Compound 26 was the standout, with the highest CB2 activity (EC = 3.665 nM) and an impressive selectivity index over CB1, along with analysis of logP values and docking simulations to understand molecular interactions.
Article Abstract
Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.
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| http://dx.doi.org/10.1016/j.ejmech.2017.05.060 | DOI Listing |
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