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Design, microwave-assisted synthesis, biological evaluation and molecular modeling studies of 4-phenylthiazoles as potent fatty acid amide hydrolase inhibitors.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-03-05 , DOI: 10.1111/cbdd.13670
Stephanie R Wilt 1 , Mark Rodriguez 1 , Thanh N H Le 1 , Emily V Baltodano 1 , Adrian Salas 1 , Stevan Pecic 1
Affiliation  

Endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti-inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids; thus, inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2-naphthyl- and 4-phenylthiazole scaffolds were identified, but up to the present time, very little structure-activity relationship studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.

中文翻译:

设计,微波辅助合成,生物学评估和分子模型研究作为有效脂肪酸酰胺水解酶抑制剂的4-苯基噻唑。

内源性大麻素,大麻素(AEA)和2-花生四烯酸甘油酯(2-AG)是激活大麻素受体的内源性脂质。这些受体的激活产生抗炎和止痛作用。脂肪酸酰胺水解酶(FAAH)是一种水解内源性大麻素的膜酶。因此,抑制FAAH是开发治疗炎症和疼痛的新疗法的一种有吸引力的方法。以前,已经确定了含有2-萘基和4-苯基噻唑骨架的强效大鼠FAAH抑制剂,但是到目前为止,对这些部分进行的结构活性关系研究很少。我们设计并合成了几种包含这些结构基序的类似物,并评估了其对人FAAH酶的抑制能力。此外,我们建立并验证了人类FAAH酶的同源性模型,并进行了对接实验。我们在低纳摩尔范围内鉴定了几种抑制剂,并计算了其ADME预测值。这些FAAH抑制剂代表了未来临床前体内研究的有希望的候选药物。
更新日期:2020-03-05
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