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Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acschemneuro.7b00239 J. Matthew Meinig 1 , Skylar J. Ferrara 1 , Tania Banerji 1 , Tapasree Banerji 1 , Hannah S. Sanford-Crane 1 , Dennis Bourdette 1 , Thomas S. Scanlan 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-18 00:00:00 , DOI: 10.1021/acschemneuro.7b00239 J. Matthew Meinig 1 , Skylar J. Ferrara 1 , Tania Banerji 1 , Tapasree Banerji 1 , Hannah S. Sanford-Crane 1 , Dennis Bourdette 1 , Thomas S. Scanlan 1
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The blood–brain barrier (BBB) can be a substantial impediment to achieving therapeutic levels of drugs in the CNS. Certain chemical functionality such as the carboxylic acid is a general liability for BBB permeability preventing significant CNS distribution of a drug from a systemic dose. Here, we report a strategy for CNS-selective distribution of the carboxylic acid containing thyromimetic sobetirome using prodrugs targeted to fatty-acid amide hydrolase (FAAH), which is expressed in the brain. Two amide prodrugs of sobetirome were shown to be efficient substrates of FAAH with Vmax/KM values comparable to the natural endocannabinoid FAAH substrate anandamide. In mice, a systemic dose of sobetirome prodrug leads to a substantial ∼60-fold increase in brain distribution (Kp) of sobetirome compared to an equimolar systemic dose of the parent drug. The increased delivery of sobetirome to the brain from the prodrug was diminished by both pharmacological inhibition and genetic deletion of FAAH in vivo. The increased brain exposure of sobetirome arising from the prodrug corresponds to ∼30-fold increased potency in brain target engagement compared to the parent drug. These results suggest that FAAH-targeted prodrugs can considerably increase drug exposure to the CNS with a concomitant decrease in systemic drug levels generating a desirable distribution profile for CNS acting drugs.
中文翻译：
用前药靶向脂肪酰胺水解酶用于中枢神经系统选择性治疗
血脑屏障（BBB）可能是实现CNS药物治疗水平的重大障碍。某些化学官能团（例如羧酸）是BBB渗透性的一般责任，它会阻止药物从全身剂量的显着CNS分布。在这里，我们报告了使用靶向脂肪酸酰胺水解酶（FAAH）的前药，在大脑中表达的CNS选择性分配含羧酸的甲状腺素钠药物的策略。结果表明，Sobeirome的两种酰胺类前药是FAAH的有效底物，其V max / K M值可与天然内源性大麻素FAAH底物anandamide比较。在小鼠中，与等摩尔全身剂量的母体药物相比，全身剂量的sobetirome前体药物导致sobetirome的脑部分布（K p）大幅提高约60倍。在体内FAAH的药理学抑制和基因删除作用均降低了前药中索贝托洛姆向大脑的递送量增加。。与母体药物相比，由前药引起的索贝地仑的脑暴露增加对应于约30倍的大脑靶标参与效力。这些结果表明，靶向FAAH的前药可以显着增加药物对中枢神经系统的暴露，同时伴随全身性药物水平的下降，从而为中枢神经系统作用药物产生理想的分布特征。
更新日期：2017-08-19
中文翻译：
用前药靶向脂肪酰胺水解酶用于中枢神经系统选择性治疗
血脑屏障（BBB）可能是实现CNS药物治疗水平的重大障碍。某些化学官能团（例如羧酸）是BBB渗透性的一般责任，它会阻止药物从全身剂量的显着CNS分布。在这里，我们报告了使用靶向脂肪酸酰胺水解酶（FAAH）的前药，在大脑中表达的CNS选择性分配含羧酸的甲状腺素钠药物的策略。结果表明，Sobeirome的两种酰胺类前药是FAAH的有效底物，其V max / K M值可与天然内源性大麻素FAAH底物anandamide比较。在小鼠中，与等摩尔全身剂量的母体药物相比，全身剂量的sobetirome前体药物导致sobetirome的脑部分布（K p）大幅提高约60倍。在体内FAAH的药理学抑制和基因删除作用均降低了前药中索贝托洛姆向大脑的递送量增加。。与母体药物相比，由前药引起的索贝地仑的脑暴露增加对应于约30倍的大脑靶标参与效力。这些结果表明，靶向FAAH的前药可以显着增加药物对中枢神经系统的暴露，同时伴随全身性药物水平的下降，从而为中枢神经系统作用药物产生理想的分布特征。
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