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)。

• 批准号: 10577008
• 负责人: Shakiru Olajire Alapafuja
• 金额: $ 32万
• 依托单位: MAKSCIENTIFIC, LLC
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10577008
• 关键词: 2-arachidonylglycerol; ABCB1 gene; Abstinence; Address; Affinity; Agonist; Behavioral; Behavioral Assay; Biochemical; Biological Assay; Biological Availability; Brain; Businesses; CNR1 gene; Cannabis; Catalepsy; Clinical Trials; Dependence; Development; Discrimination; Dose; Drug Design; Drug Kinetics; Endocannabinoids; Enzyme Inhibition; Enzymes; Evaluation; Exclusion; Exhibits; FDA approved; Generations; Goals; Government; Hepatic; Human; In Vitro; Incidence; Isoenzymes; Lead; Ligands; MAGL inhibitor; Marijuana; Mediating; Medical; Medication Management; Metabolic; Microsomes; Mission; Monkeys; Monoacylglycerol Lipases; Nabilone; National Institute of Drug Abuse; Oral; Parents; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Physiological; Plasma; Property; Public Health; Rattus; Recreation; Reporting; Research; Rodent; Science; Selection Criteria; Self Administration; Smoke; Solubility; Stimulus; Symptoms; Testing; Therapeutic; Time; Universities; Withdrawal; Withdrawal Symptom; Work; anandamide; aqueous; behavioral study; cannabimimetics; cannabinergic; cannabis withdrawal; cheminformatics; clinical application; commercialization; design; drug development; drug discovery; drug discrimination; drug synthesis; endogenous cannabinoid system; fatty acid amide hydrolase; improved; in vivo; in vivo evaluation; marijuana use; marijuana use disorder; multidisciplinary; natural hypothermia; nonhuman primate; novel; novel therapeutic intervention; pharmacologic; phase 2 study; preclinical trial; professor; response; scale up; side effect

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 – 第 7 单元 – 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， 缺乏批准的药物是 NIDA 使命的一个主要焦点。 CUD 的治疗包括直接作用的 CB1 激动剂，例如 Δ9-THC 或大麻龙，这些药物已被 据报道可减少人类的大麻戒断症状，​​支持基于激动剂的治疗效用 然而，直接作用的 CB1 受体激动剂的使用很复杂。 不良的拟大麻作用，包括不稳定的药代动力学、不良的生理和主观影响 与吸食大麻的影响重叠，并且具有相当大的依赖性。 基于激动剂的 CUD 治疗方法的开发途径可能在于间接增强大麻素能的药物 活性，例如通过抑制代谢酶脂肪酸酰胺水解酶 (FAAH) 和单酰基甘油 脂肪酶（MAGL）可增加大脑中内源性大麻素 N-花生四烯酰乙醇胺（anandamide， 我们的初步研究结果分别强化了这一观点。 猴子中的 CB1 歧视研究表明，联合抑制 FAAH 和 MAGL，但两者均不起作 用 单独使用，可以产生类似 Δ9-THC 的内感受作用。最近，我们发现了第二代双重作用。 与母体双 FAAH-MAGL 相比，FAAH-MAGL 抑制剂 MAK2376 具有改善的成药性 抑制剂 AM4302，即 MAK2376 对肝微粒体表现出更高的稳定性和更高的水溶性 受这些发现的鼓舞，我们计划优化药代动力学和药理学。 通过设计、合成和评估体外和体内新型衍生物来确定 MAK2376 的参数 将测试新型高效配体的微粒体稳定性、水溶性和 体内研究配体的选择标准包括：IC50<10 nM (r/hFAAH)，<500 nM (r/hMAGL)；不同的 rFAAH/rMAGL 抑制比，（例如，1/10、1/50、1/100）；CB1：Ki >300 nM； 稳定性，t1/2（分钟）>15（m，r）和>30（人）；水溶性（pH 7.4）>60 ug/m； >25% 且脑/血浆比率 >50% 将测试选定化合物的体内四分体和 CB1 辨别能力。 我们的首要目标是发现改进的混合作用 FAAH-MAGL 抑制剂 在产生最小 CB1 相关四联体副作用的剂量下产生类似 Δ9-THC 的刺激效应（例如， 最有前途的 2-4 种配体将进入非人类 II 期研究。 我们预计新型混合作用 FAAH-MAGL 抑制剂将在灵长类动物中得到进一步优化。 在非人类灵长类动物中取得第一阶段和高度转化的第二阶段研究的成功将是“领先” 将在临床前和临床试验中进一步研究作为 CUD 候选药物的化合物。 由科学和商业专家组成的多学科团队非常适合成功推进该项目 商业化第二阶段。