From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis

作者：Beier Jiang, Xingwu Jiang, Qiansen Zhang, Qiuwen Liang, Zi-Liang Qiu, Xiang-Bai Sun, Junjie Yang, Si Chen, Chunyang Yi, Xiaolei Chai, Mingyao Liu, Li-Fang Yu, Weiqiang Lü, Hankun Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c01023 · 被引用次数：19 · 研究领域：Cannabis and Cannabinoid Research、Hops Chemistry and Applications、Mast cells and histamine

Synthetic cannabinoids, as exemplified by SDB-001 ( 1 ), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (−)- trans -Δ 9 -tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1 H -pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure–activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.