PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

新型戒烟药物的临床前开发

• 批准号: 8715436
• 负责人: Nurulain T Zaveri
• 金额: $ 75.79万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715436
• 关键词: ADME Study; Abstinence; Advanced Development; Adverse effects; Affect; Affinity; Agonist; Alcohols; Animal Model; Area; Autonomic ganglion; Binding; Biological Assay; Boxing; Brain; Bupropion; Canis familiaris; Cardiac; Cardiopulmonary; Cardiovascular system; Chantix; Clinical; Data; Development; Digit structure; Dose; Drug Formulations; Drug Kinetics; Ensure; Food; Future; Gene Cluster; Genetic Polymorphism; Goals; Habenula; Human; Human Genetics; In Vitro; Intake; Lead; Ligands; Medial; Metabolic; Mind; Modeling; Molecular; Nicotine; Nicotine Dependence; Nicotinic Receptors; Oral; Outcome; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Plasma; Play; Positioning Attribute; Process; Rattus; Relapse; Reporting; Research; Risk; Role; Safety; Self Administration; Series; Small Business Innovation Research Grant; Smoking; Smoking Behavior; Staging; Testing; Therapeutic; Toxicology; addiction; base; drug candidate; drug development; genetic association; in vivo; interpeduncular nucleus; lead series; nicotine replacement; novel; novel strategies; pre-clinical; public health relevance; research study; safety study; scale up; small molecule; smoking cessation; varenicline

DESCRIPTION (provided by applicant): The goal of the proposed Phase II SBIR is to advance a novel class of alpha3beta4 nicotinic acetylcholine receptor antagonists (new molecular entities), which show excellent in vivo efficacy in blocking nicotine self- administratio and reinstatement of nicotine seeking, towards development as smoking cessation therapy. We have discovered a series of highly potent alpha3beta4 nAChR functional antagonists, all of which have single-digit nanomolar binding affinity and >100-fold target selectivity versus the closely related 42 and 7 nAChR subtypes. In our successful Phase I effort, we showed that three lead compounds from this series not only significantly block nicotine self-administration in rats, at low doses, without effect on food responding, but also block reinstatement of nicotine seeking, an animal model of relapse. The significant efficacy of these selective alpha3beta4 nAChR ligands strongly suggests that alpha3beta4 nAChR functional antagonism' is a promising pharmacological mechanism for smoking cessation pharmacotherapy. We have achieved all of the Aims of our Phase I SBIR and conducted additional studies to support the suitability of this class of compounds for further drug development. We now seek Phase II support to advance an optimized set of lead candidates, through a series of 'de-risking' experiments, with the goal of selecting a 'development candidate' for the proposed indication (smoking cessation). A second goal is to position at least one other compound in our series as backup for the same indication or as a future development candidate for other indications. In Aim 1, we will scale-up (non-GMP) a panel of optimized alpha3beta4 nAChR ligands for preformulation and development activities. In Aim 2, the development candidates will be characterized in a series of ADME studies and PK in two species. In Aim 3, confirmation of oral efficacy of the selected candidates will be determined in a rat model of nicotine self-administration and reinstatement of nicotine-seeking. In Aim 4, we will carry out detailed safety pharmacology and early toxicology studies including GLP cardiovascular safety for dog, functional observational battery and Range-finding toxicology in two species. The desired outcome of this project will be the selection of the most suitable 'development candidate', which will be immediately ready for definitive GLP toxicology studies for an IND submission and advancement as smoking cessation pharmacotherapy.

描述（由申请人提供）：拟议的II期SBIR的目的是促进一类新型的Alpha3beta4烟碱乙酰胆碱受体拮抗剂（新分子实体），在阻止尼古丁自我倾向和恢复尼古丁寻求尼古丁寻求尼古丁的体内表现出极好的疗效，以开发蛋白质，以促进蛋白质的研究。我们发现了一系列高度有效的alpha3beta4 NACHR功能拮抗剂，所有拮抗剂均具有单位纳摩尔结合亲和力和> 100倍的目标选择性，而与密切相关的42和7 NACHR子类型相比。在我们成功的第一阶段努力中，我们展示了该系列的三种铅化合物不仅显着阻止大鼠的尼古丁自我给药，低剂量，对食物反应的影响，而且还阻止了恢复尼古丁寻求的恢复，这是一种复发的动物模型。这些选择性alpha3beta4 NACHR配体的显着疗效强烈表明alpha3beta4 NACHR功能拮抗作用是一种有希望的戒烟药理机制，用于戒烟药物治疗。我们已经实现了第一阶段SBIR的所有目标，并进行了其他研究，以支持此类化合物对进一步药物开发的适用性。现在，我们寻求第二阶段的支持，通过一系列“疾病”实验推进一组优化的铅候选者，目的是为提出的适应症（戒烟）选择“开发候选者”。第二个目标是将至少在我们系列的其他化合物中定位为相同指示的备份，或作为其他指示的未来发展候选人。在AIM 1中，我们将扩大（非GMP）一组优化的Alpha3beta4 NACHR配体，以进行预构和开发活动。在AIM 2中，将在两种物种中的一系列ADME研究和PK中表征发展候选者。在AIM 3中，将确认所选候选者的口服功效，将在尼古丁自我给药和恢复尼古丁寻求的大鼠模型中确定。在AIM 4中，我们将进行详细的安全药理学和早期毒理学研究，包括狗的GLP心血管安全，功能性观察电池和两种物种的范围调查毒理学。该项目的期望结果将是最合适的“发展候选者”的选择，该项目将立即准备好进行确定的GLP毒理学研究，以进行IND提交和进步作为戒烟药物治疗。