Optimization and preclinical development of FAAH inhibitors for smoking cessation

描述(由申请人提供)：我们已经证明，对ANANDAME降解酶，脂肪酸酰胺水解酶(FAAH)的药理抑制，可以阻止尼古丁的自我给药，并防止尼古丁诱导松鼠猴子恢复尼古丁诱导的恢复，这是人类尼古丁成瘾和尼古丁复发的模型。基于这些结果，表明FAAH是烟草依赖的一个有前途的分子靶点，我们建议进行一项旨在FAAH的优化和临床前开发的药物发现计划。 用于戒烟的抑制剂。我们的建议有两个主要目标：具体目标1：优化FAAH抑制剂和确定临床前戒烟候选药物。我们将从大院开始进行领先的优化活动 URB694，是我们实验室以前发现的一种有效的FAAH抑制剂。化合物将在体外和体内合成和测试，收集的信息将用于设计新分子，直到选择出具有合适疗效和安全性的临床前候选药物。 具体目标2：FAAH戒烟抑制剂的临床前开发。我们将(A)推进目标1中确定的候选药物的临床前开发；(B)为以戒烟为治疗目标的候选药物准备和提交研究新药(IND)申请；(C)在IND获得批准后，寻求私人和/或公共赞助商支持人体安全性和概念验证研究。为了实现这些目标，我们组建了一个多学科联盟，将科学上的卓越与工业药物发现和临床前开发方面的经验结合起来。该团队包括FAAH抑制领域的领导者、科学家和企业家Daniele Piomelli(UCI)；尼古丁研究的先驱、行为药理学家Steven Goldberg(NIDA-IRP)；高级化学家Tiziano Bandiera(IIT)；高级药理学家Angelo Reggiani(IIT)；以及临床前开发专家Edward Monaghan。因此，o

DESCRIPTION (provided by applicant): We have shown that pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), blocks nicotine self-administration and prevents nicotine-induced reinstatement in squirrel monkeys, a model of human nicotine addiction and relapse to nicotine use. Based on these results, which point to FAAH as a promising molecular target for tobacco dependence, we propose to undertake a drug discovery program aimed at the optimization and preclinical development of FAAH inhibitors for smoking cessation. Our proposal has two primary goals: Specific Aim 1: Optimization of FAAH inhibitors and identification of a preclinical candidate for smoking cessation. We will conduct a lead optimization campaign starting from the compound URB694, a potent FAAH inhibitor previously identified in our laboratory. Compounds will be synthesized and tested in vitro and in vivo, and information collected will be used to design new molecules until a preclinical candidate with suitable efficacy and safety profile is selected. Specific Aim 2: Preclinical development of FAAH inhibitors for smoking cessation. We will (a) advance through preclinical development the candidate identified in Aim 1; (b) prepare and submit an Investigational New Drug (IND) application for the candidate with smoking cessation as therapeutic target; (c) seek private and/or public sponsors to support safety and proof-of-concept studies in humans after IND approval. To achieve these goals, we have assembled a multi-disciplinary consortium that unites scientific excellence with experience in industrial drug discovery and preclinical development. The team includes scientist and entrepreneur Daniele Piomelli (UCI), a leader in the field of FAAH inhibition; behavioral pharmacologist Steven Goldberg (NIDA-IRP), a pioneer in nicotine research; senior chemist Tiziano Bandiera (IIT); senior pharmacologist Angelo Reggiani (IIT); and preclinical development expert Edward Monaghan. Thus, o