Dual Fatty Acid Amide Hydrolase (FAAH)/Monoacylglycerol lipase (MAGL) Inhibitors for Cannabis Use Disorder (CUD).

双脂肪酸酰胺水解酶 (FAAH)/单酰基甘油脂肪酶 (MAGL) 抑制剂,用于治疗大麻使用障碍 (CUD)。

基本信息

  • 批准号:
    10577008
  • 负责人:
  • 金额:
    $ 32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

OTHER PROJECT INFORMATION – Unit 7 – Project Summary/Abstract This project addresses the growing need for medications for cannabis use disorder (CUD) which, in the absence of approved medications, is a major focus of NIDA’s mission. Currently available cannabinergic-based treatments for CUD include the directly acting CB1 agonists, e.g., Δ9-THC or nabilone, which have been reported to reduce cannabis withdrawal symptoms in humans supporting the therapeutic utility of agonist-based medications for management of CUD. However, the use of directly acting CB1 receptor agonists is complicated by adverse cannabimimetic effects, including erratic pharmacokinetics, unwanted physiological and subjective effects that overlap with those of smoked marijuana, and considerable dependence liability. An alternate avenue for developing agonist-based treatments for CUD may lie in drugs that indirectly enhance cannabinergic activity, e.g., by inhibiting the metabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) to increase brain levels of the endocannabinoids N-arachidonoylethanolamine (anandamide, AEA) or 2-arachidonylglycerol (2-AG), respectively. This view is strengthened by our preliminary findings from CB1-discrimination studies in monkeys showing that combined inhibition of FAAH and MAGL, but neither action alone, can produce Δ9-THC-like interoceptive effects. More recently, we identified a second-generation dual FAAH-MAGL inhibitor MAK2376 with improved druggability profile compared to the parent dual FAAH-MAGL inhibitor AM4302, i.e., MAK2376 showed greater stability to hepatic microsomes and higher aqueous solubility relative to AM4302. Encouraged by these findings, we plan to optimize pharmacokinetic and pharmacological parameters of MAK2376 by designing, synthesizing, and evaluating novel derivatives in vitro and in vivo assays. Novel high potency ligands will be tested in microsomal stability, aqueous solubility, and pharmacokinetic assays. Criteria for selecting ligands for in vivo studies include: IC50<10 nM (r/hFAAH), <500 nM (r/hMAGL); varying rFAAH/rMAGL inhibition ratio, (e.g.,1/10, 1/50, 1/100); CB1: Ki >300 nM; microsomal stability, t1/2 (minutes) >15 (m, r) and >30 (human); aqueous solubility (pH 7.4) >60 ug/m; oral bioavailability >25% and brain/plasma ratio >50%. Select compounds will be tested in vivo tetrad and CB1 discrimination assays in rats. Our overarching goal will be to discover improved mixed-action FAAH-MAGL inhibitors that produce Δ9-THC-like stimulus effects at doses that produce minimal CB1-associated tetrad side-effects (e.g., hypothermia/catalepsy). The most promising 2-4 ligands will be advanced to Phase II studies in nonhuman primates for further optimization. We anticipate that novel mixed-action FAAH-MAGL inhibitors that are successful in this Phase I and highly translational Phase II studies in nonhuman primates will be ‘lead’ compounds that will be further studied in preclinical and clinical trials as candidate medications for CUD. Our multidisciplinary team of scientific and business experts is well suited to successfully advance this project to commercialization phase II.
其他项目信息-单元7-项目摘要/摘要 该项目解决了对大麻使用障碍(CUD)药物日益增长的需求,在 缺乏经批准的药物,是NIDA使命的一个主要重点。目前可用的大麻能类药物 对CUD的治疗包括直接作用的cb1激动剂,例如Δ9-thc或nablone,它们已经被 据报道,可减少人类的大麻戒断症状,支持激动剂的治疗作用 治疗慢性阻塞性肺疾病的药物。然而,直接作用的CB1受体激动剂的使用是复杂的。 由于不良的拟大麻效应,包括不稳定的药代动力学、不受欢迎的生理和主观 与吸食大麻的效果重叠,并有相当大的依赖倾向。替补 开发以激动剂为基础的治疗CUD的途径可能在于间接增强大麻能的药物 活性,例如通过抑制代谢酶脂肪酸酰胺水解酶(FAAH)和单酰甘油 脂肪酶(MAGL),以增加大脑中内源性大麻素N-花生四烯基乙醇胺(ANANDAME, AEA)或2-花生四烯基甘油(2-AG)。我们的初步发现强化了这一观点。 对猴子的CB1辨别研究表明FAAH和MAGL联合抑制,但两者都不起作用 单独使用,可产生Δ-9-Thc样内感受性效应。最近,我们发现了第二代双星 FAAH-MAGL抑制剂MAK2376与双亲FAAH-MAGL相比具有更好的药效性 抑制剂AM4302,即MAK2376对肝微粒体具有较高的稳定性和较高的水溶解度 相对于AM4302。受到这些发现的鼓舞,我们计划优化药代动力学和药理学 MAK2376在体内外设计、合成和评价新衍生物的参数 化验。新型高效配体将在微粒体稳定性、水溶解性和 药代动力学分析。选择体内研究配体的标准包括:IC50;10 NM(r/hFAAH),&lt;500 NM(r/hMAGL);不同的rFAAH/rMAGL抑制比(如1/10、1/50、1/100);CB1:KI和GT;300 nM;微粒体 稳定性,t1/2(分钟)&gt;15(m,r)和&gt;30(人);水溶解度(pH 7.4)&gt;60 ug/m;口服生物利用度 &gt;25%和脑/血浆比&gt;50%。选定的化合物将在体内进行四分体和CB1识别测试 在大鼠身上进行检测。我们的首要目标将是发现改进的混合作用FAAH-MAGL抑制剂 以产生最小Δ相关四分体副作用的剂量产生CB19-THc样刺激效应(例如, 体温过低/嗜睡)。最有希望的2-4个配体将进入非人类第二阶段研究 灵长类动物进行进一步优化。我们预计新的混合作用FAAH-MAGL抑制剂是 在非人类灵长类动物中成功进行这一阶段的第一阶段和高度翻译的第二阶段研究将是“领先的” 将在临床前和临床试验中作为CUD候选药物进行进一步研究的化合物。我们的 多学科的科学和商业专家团队非常适合成功地将该项目推进到 商业化阶段II。

项目成果

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Shakiru Olajire Alapafuja其他文献

Shakiru Olajire Alapafuja的其他文献

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{{ truncateString('Shakiru Olajire Alapafuja', 18)}}的其他基金

NAAA Inhibitors as Anti-inflammatory Agents, Phase II
NAAA 抑制剂作为抗炎剂,II 期
  • 批准号:
    9201955
  • 财政年份:
    2015
  • 资助金额:
    $ 32万
  • 项目类别:
Cannabinergic Receptor Antagonists for Nicotine Addiction
大麻素受体拮抗剂治疗尼古丁成瘾
  • 批准号:
    8713752
  • 财政年份:
    2014
  • 资助金额:
    $ 32万
  • 项目类别:

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  • 财政年份:
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