From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis
From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis
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DOI：
10.1021/acs.jmedchem.0c01023
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发表时间：
2021-01-14
影响因子：
7.3
通讯作者：
Zhang, Han-Kun
中科院分区：
文献类型：
--
作者：
Jiang, Bei-Er;Jiang, Xingwu;Zhang, Han-Kun
以SDB-001(1)为例，人工合成的大麻素与CB1和CB2受体结合，并发挥与大麻植物中存在的主要精神活性成分(-)-反式-三角洲(9)-四氢大麻酚相似的拟大麻效果。由于CB1受体配体被发现具有严重的不良精神影响，人们将更多的注意力转向开发CB2受体的潜在治疗价值。在寻找新型和选择性CB2受体激动剂的过程中，我们选择1作为HIT分子鉴定的起点，设计、合成了一类1H-吡唑-3-甲酰胺类化合物，并对其进行了生物活性评价。系统的构效关系研究表明，最有希望的化合物66是一种具有良好药代动力学特征的选择性CB2受体激动剂。特别是，66治疗显著减轻博莱霉素诱导的系统性硬化症小鼠模型的真皮炎症和纤维化，支持CB2受体激动剂可能作为治疗系统性硬化症的潜在疗法。
Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Delta(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 1H-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.