Pyrazole antagonists of the CB1 receptor with reduced brain penetration
Pyrazole antagonists of the CB1 receptor with reduced brain penetration
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DOI：
10.1016/j.bmc.2016.01.033
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发表时间：
2016-03-01
影响因子：
3.5
通讯作者：
Maitra, Rangan
中科院分区：
文献类型：
--
作者：
Fulp, Alan;Zhang, Yanan;Maitra, Rangan
1型大麻素受体（CB1）拮抗剂可能对治疗肥胖、肝病、代谢综合征和血脂异常有用。不幸的是，中枢神经系统（CNS）中CB1的抑制会产生不良反应，包括一些患者的抑郁、焦虑和自杀意念，这导致吡唑逆激动剂利莫那班（SR141716A）从欧洲市场下架。目前正在努力生产外周选择性CB1拮抗剂，以规避中枢神经系统相关的不良反应。在这项研究中，探索了利莫那班(1)的新型类似物，其中1-氨基哌啶基团被转换为4-氨基哌啶，连接在4-氨基位置(5)。哌啶氮与氨基甲酸酯、酰胺和磺胺类化合物被功能化，提供了有效的hCB1逆激动剂，对hCB1比hCB2具有良好的选择性。通过体外脑渗透、口服吸收和代谢稳定性模型进一步研究所选化合物。几种化合物被确定为预测最小的脑穿透和良好的代谢稳定性。体内药代动力学测试显示，与利莫那班相比，逆激动剂8c是口服生物可利用的，并且大大降低了脑渗透。(C) 2016 Elsevier Ltd.版权所有。
Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant. (C) 2016 Elsevier Ltd. All rights reserved.