Discovery next generation inhibitors of ALDH2 to reduce craving and alcohol consumption in alcohol use disorders

项目摘要 酒精使用障碍（AUD）影响全球7600万成年人，其中包括1800万美国人， 对严重的医疗、心理、社会、经济和个人问题负责（1）。经济总 在美国，澳元每年给社会带来的成本高达2240亿美元（2）。总共330亿美元是 每年用于治疗物质使用障碍（SUD）的费用不到4%， 药物治疗（3）。双硫仑，ALDH 2和ALDH 1的非竞争性、不可逆（自杀）抑制剂（4）（5） 已用于治疗AUD超过50年（6）。不幸的是，双硫仑是一种更有效的 ALDH 1也抑制ALDH 5，并且似乎非选择性地与许多其他酶和蛋白质结合， 不良脱靶效应（7）。显然，对更好的治疗和更大的利用率的需求尚未得到满足， 安全有效的药物治疗AUD的机会很大。 AUD是一种复杂的疾病。Koobow和Koob（8）假设多巴胺（DA）的激增会驱动渴望， 通过奖励回路的成瘾行为（9）。引发对酒精渴望的条件反应激发了 寻求毒品的行为往往导致大量使用。事实上，强烈的渴望可以持续很长一段时间后，药物使用， 停止（8）。酒精和其他成瘾剂刺激丘脑核中DA水平的增加， 它似乎介导大脑中的奖励或强化过程（10）（11）（12）。 醛脱氢酶2（ALDH 2）的选择性、可逆的抑制已经显示i）减少自身- 给予酒精，尼古丁，可卡因和瑞芬太尼（13）（14）（15）; ii）减少线索恢复 酒精、可卡因、甲基苯丙胺（13）（14）和海洛因（16）; iii）减少对碳水化合物的异常渴望 和脂肪酸（17）;和iv）防止酒精戒断焦虑以及其他焦虑原因（18）。最近， 在小鼠中敲除ALDH 2活性减少了总饮酒量和狂饮（19）。此外，委员会认为， 杂合子或纯合子或ALDH 2 *2等位基因的个体具有显著降低的活性或缺乏活性 与野生型ALDH 2基因携带者相比，ALDH 2基因携带者和AUD风险较低，但不影响寿命（20） （二十一）、显然，ALDH 2活性降低降低了AUD的风险。此外，我们发表的临床前研究结果 这表明对治疗其他成瘾性疾病具有额外价值。 我们的目标是实施创新的筛选技术，发明新的化合物， 有效、选择性和可逆的ALDH 2抑制剂，用于安全治疗AUD患者。药物 优化是一项多目标的工作，是一个迭代过程， 期望的（ALDH 2抑制）和不期望的性质的活性关系。这一过程将得到以下方面的帮助： 计算机辅助设计和药效团建模（33）。 1

PROJECT SUMMMARY Alcohol use disorder (AUD) affects 76 million adults world-wide, including 18 million Americans, and is responsible for serious medical, psychological, social, economic, and personal problems (1). The total economic cost of AUD to society is a staggering $224 billion each year in the United States (2). A total of $33 billion is spent each year to treat substance use disorder (SUD), with less than 4% of treatment spending for pharmacotherapy (3). Disulfiram, a noncompetitive, irreversible (suicide) inhibitor of ALDH2 and ALDH1 (4) (5) has been used to treat AUD for more than 50 years (6). Unfortunately, disulfiram is a more potent inhibitor of ALDH1, also inhibits ALDH5, and appears to bind non-selectively to many other enzymes and proteins, leading to adverse off-target effects (7). There is a clear unmet need for better treatments and greater utilization, with a large opportunity for safe and effective pharmacotherapies to treat AUD. AUD is a complex disorder. Volkow and Koob (8) postulate that a surge of dopamine (DA) drives craving and addictive behavior through reward circuits (9). Conditioned responses that trigger craving for alcohol motivate drug-seeking behaviors often leading to heavy use. Indeed, strong cravings can persist long after drug use has stopped (8). Alcohol and other addictive agents stimulate an increase in DA levels in the nucleus accumbens, which appears to mediate reward or reinforcement processes in brain (10) (11) (12). Selective, reversible, inhibition of aldehyde dehydrogenase 2 (ALDH2) has been shown to i) reduce self- administration of alcohol, nicotine, cocaine, and remifentanil (13) (14) (15); ii) reduce cue-reinstatement of alcohol, cocaine, methamphetamine (13) (14), and heroin (16); iii) reduce abnormal cravings for carbohydrate and fatty acids (17); and iv) prevents alcohol withdrawal anxiety as well as other causes of anxiety (18). Recently, a knockout of ALDH2 activity in mice reduces both total drinking of alcohol and binge drinking (19). Furthermore, individuals who are hetero- or homozygous or for the ALDH2*2 allele have markedly reduced or absent activity of ALDH2 and a lower risk of AUD, without affecting longevity, compared to wild-type ALDH2 gene carriers (20) (21). Clearly, decreased ALDH2 activity lowers the risk of AUD. In addition, our published preclinical findings suggest additional value for treating other addiction disorders. Our objective is to implement an innovative screening technology to invent new compounds that are potent, selective, and reversible inhibitors of ALDH2 for the safe treatment of patients with AUD. Drug optimization is a multi-objective undertaking and is an iterative process that integrates knowledge of structure- activity relationships for desired (ALDH2 inhibition) and undesired properties. This process will be aided by computer aided design and pharmacophore modelling (33). 1