Development of Novel Drugs for Smoking Cessation Pharmacotherapy

戒烟药物治疗新药的开发

• 批准号: 8315565
• 负责人: Nurulain T Zaveri
• 金额: $ 29.33万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315565
• 关键词: ADME Study; Address; Adverse effects; Affect; Affinity; Agonist; Animal Model; Back; Behavior; Behavior Therapy; Binding; Biological Assay; Blood; Brain; Bupropion; Centers for Disease Control and Prevention (U.S.); Clinic; Clinical; Clinical Trials; Country; Cues; Data; Dependence; Developing Countries; Development; Digit structure; Dose; Drug Delivery Systems; Economic Burden; Effectiveness; Evaluation; Food; Future; Gene Cluster; Genetic; Genetic Polymorphism; Goals; Health; In Vitro; Knockout Mice; Laboratory Animal Models; Lead; Legal patent; Ligands; Link; Mecamylamine; Metabolic; Modeling; Nicotine; Nicotine Dependence; Nicotine Inhaler; Nicotine Nasal Spray; Nicotine Withdrawal; Nicotinic Receptors; Penetration; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Plasma; Play; Program Development; Rattus; Relapse; Reporting; Research; Risk; Role; Safety; Screening procedure; Self Administration; Series; Single Nucleotide Polymorphism; Small Business Innovation Research Grant; Smoker; Smoking; Smoking Behavior; Societies; Therapeutic; Time; Tobacco; Tobacco Dependence; Tobacco use; Toxicology; Translations; Validation; Withdrawal; base; comparative efficacy; design; drug candidate; drug development; drug relapse; economic cost; efficacy evaluation; genetic association; health economics; improved; in vivo; mortality; nicotine gum; nicotine patch; novel; pre-clinical; small molecule; smoking cessation; success; tool; varenicline

DESCRIPTION (provided by applicant): The overall goal of this SBIR Phase I project is to identify at least two suitable, efficacious preclinical candidates from our novel series of very potent and highly selective ¿3¿4 nicotinic acetylcholine receptor (nAChR) ligands, for further translational development into smoking cessation medications. The promising in vivo efficacy of the highly selective ¿3¿4 nAChR antagonist compound from this series in significant blocking nicotine self-administration in rats, at low doses, with no effect on food responding, strongly supports our hypothesis that '¿3¿4 nAChR antagonism' is a promising new pharmacological mechanism for smoking cessation pharmacotherapy, and supports the proposed preclinical ADME assessment and efficacy studies to identify two suitable preclinical candidates from this series for further development. Although there is evidence that success rates for quitting smoking, are 2-3 times higher when pharmacotherapy is used than when no treatments are used, the repertoire of current pharmacotherapies is extremely limited. With the enormous health and economic burdens that smoking has on our society, and notwithstanding the limited efficacy and emerging side-effects of the few currently available smoking cessation medications, development of new medications for smoking cessation, particularly against new pharmacological targets, is a critical need, to decrease the impact of smoking on health and mortality. Although it is known that the reinforcing and addictive effects of nicotine are due to is actions on the nicotinic acetylcholine receptors, a major barrier in the field has been the identification of the various nAChR subtypes that play a role in the various aspects of nicotine dependence, and their validation as drug targets. This has been exacerbated by lack of subtype-selective nAChR ligands that can be used as tools or developed as therapeutics. Several recent studies suggest that the ¿3¿4 subtype of the nAChR is important for several aspects of nicotine dependence. Recent genetic association studies show that single nucleotide polymorphisms (SNPs) in the gene cluster CHRNA5/A3/B4, encoding for the ¿3, ¿5 and ¿4 nAChR subunits are associated with increased risk for heavy smoking, inability to quit, and increased sensitivity to nicotine. Furthermore, the ¿4 nAChR subunit has been shown to be necessary for nicotine withdrawal. The promising in vivo efficacy of our highly selective ¿3¿4 nAChR antagonist suggests that ¿3¿4 antagonism may be a promising target for smoking cessation and appears to be consistent with the recent genetic studies on the role of the ¿3¿4 subtype. Based on these results, we propose, in this application, a preclinical development program to evaluate this compound series in in vitro ADME studies and in vivo biovailability and blood-brain penetration assays (Aim 1), to select two candidate compounds for full efficacy evaluation in animal models of nicotine self-administration and reinstatement (a model of drug relapse) (Aim 2). Lead optimization to improve the drug-like suitability of the initial series of compounds is also proposed (Aim 3). Our Specific Aims are designed as a first step toward the preclinical development of this promising class of compounds as pharmacotherapies for tobacco dependence. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed research is to develop our novel ¿3¿4 nAChR antagonists as smoking cessation medications against a new target, the ¿3¿4 nAChRs, which have been recently implicated in several genetic studies, to be involved in smoking behaviors and withdrawal. Our exciting preliminary data shows that our lead compound dramatically inhibits nicotine self-administration in laboratory animal models. It is our ultimate goal to take this promising series of compounds into the clinic, and to provide a new, safe therapeutic option to assist smokers who wish to quit. Successful completion of this project will be the first step in this clinical translation of our promising discoveries, for the development of pharmacotherapies for smoking cessation.

描述（由申请人提供）：该 SBIR 第一阶段项目的总体目标是从我们的一系列非常有效和高度选择性的 ¿3¿4 烟碱乙酰胆碱受体 (nAChR) 配体中确定至少两种合适、有效的临床前候选药物，以进一步转化为戒烟药物。该系列的高选择性 ¿3¿4 nAChR 拮抗剂化合物在低剂量下显着阻断大鼠尼古丁自我给药，且对食物反应没有影响，其在体内的疗效有希望，有力地支持了我们的假设，即“3¿4 nAChR 拮抗作用”是戒烟药物治疗的一种有前途的新药理学机制，并支持所提出的临床前 ADME 评估和 功效研究，从该系列中确定两种合适的临床前候选药物以供进一步开发。尽管有证据表明，使用药物疗法的戒烟成功率比不使用治疗的戒烟成功率高 2-3 倍，但目前的药物疗法极其有限。由于吸烟给我们的社会带来了巨大的健康和经济负担，尽管目前可用的少数戒烟药物的功效有限且不断出现副作用，但迫切需要开发新的戒烟药物，特别是针对新的药理学目标，以减少吸烟对健康和死亡率的影响。尽管众所周知，尼古丁的增强和成瘾作用是由于其对烟碱乙酰胆碱受体的作用，但该领域的主要障碍是鉴定在尼古丁依赖的各个方面发挥作用的各种 nAChR 亚型，以及将它们作为药物靶点进行验证。由于缺乏可用作工具或开发为治疗药物的亚型选择性 nAChR 配体，这一问题更加严重。最近的几项研究表明，nAChR 的 ¿3¿4 亚型对于尼古丁依赖的几个方面很重要。最近的遗传关联研究表明，编码 3、5 和 4 nAChR 亚基的基因簇 CHRNA5/A3/B4 中的单核苷酸多态性 (SNP) 与重度吸烟、无法戒烟和对尼古丁敏感性增加的风险增加相关。此外，4 nAChR 亚基已被证明是尼古丁戒断所必需的。我们的高选择性 ¿3¿4 nAChR 拮抗剂的有前景的体内功效表明 ¡3¿4 拮抗作用可能是戒烟的有希望的目标，并且似乎与最近关于 ¡3¿4 亚型的作用的遗传学研究一致。基于这些结果，我们在本申请中提出了一个临床前开发计划，在体外 ADME 研究和体内生物利用度和血脑渗透测定中评估该化合物系列（目标 1），以选择两种候选化合物在尼古丁自我给药和恢复（药物复发模型）动物模型中进行全面功效评估（目标 2）。还提出了先导化合物优化以提高初始系列化合物的类药适用性（目标 3）。我们的具体目标旨在作为这一类有前途的化合物作为烟草依赖药物疗法的临床前开发的第一步。 公共健康相关性：拟议研究的总体目标是开发我们的新型 3¿4 nAChR 拮抗剂作为针对新靶点 3¿4 nAChR 的戒烟药物，该新靶点最近在多项遗传学研究中被证实与吸烟行为和戒断有关。我们令人兴奋的初步数据表明，我们的先导化合物可显着抑制实验动物模型中的尼古丁自我给药。我们的最终目标是将这一系列有前景的化合物带入临床，并提供一种新的、安全的治疗选择来帮助希望戒烟的吸烟者。该项目的成功完成将是我们有希望的发现临床转化的第一步，以开发 戒烟的药物疗法。