PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

新型戒烟药物的临床前开发

• 批准号: 8848367
• 负责人: Nurulain T Zaveri
• 金额: $ 74.21万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848367
• 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; Genetic study; Goals; Habenula; Health; 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; 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（由申请方提供）：拟定II期SBIR的目的是推进一类新型α 3 β 4烟碱乙酰胆碱受体拮抗剂（新分子实体），其在阻断尼古丁自我给药和尼古丁寻求恢复方面显示出优异的体内疗效，以开发为戒烟治疗。我们已经发现了一系列高效的α 3 β 4 nAChR功能性拮抗剂，所有这些拮抗剂与密切相关的42和7 nAChR亚型相比具有个位数纳摩尔结合亲和力和>100倍的靶向选择性。在我们成功的第一阶段工作中，我们表明，来自该系列的三种先导化合物不仅在低剂量下显著阻断大鼠的尼古丁自我给药，对食物反应没有影响，而且还阻断尼古丁寻求的恢复，这是一种复发的动物模型。这些选择性α 3 β 4 nAChR配体的显著功效强烈表明，α 3 β 4 nAChR功能性拮抗作用是戒烟药物治疗的有希望的药理学机制。我们已经实现了I期SBIR的所有目标，并进行了额外的研究，以支持这类化合物用于进一步药物开发的适用性。我们现在寻求第二阶段的支持，通过一系列“去风险”实验，推进一组优化的主要候选药物，目标是为拟议适应症（戒烟）选择一种“开发候选药物”。第二个目标是在我们的系列中定位至少一种其他化合物，作为相同适应症的备份或作为其他适应症的未来开发候选者。在目标1中，我们将扩大（非GMP）一组优化的alpha3 beta4 nAChR配体，用于预配制和开发活动。在目标2中，将在一系列ADME研究和两个种属的PK中表征开发候选药物。在目标3中，将在尼古丁自我给药和尼古丁寻求恢复的大鼠模型中确定所选候选药物的口服疗效。在目标4中，我们将进行详细的安全性药理学和早期毒理学研究，包括犬的GLP心血管安全性、功能观察组合和两个种属的剂量范围探索毒理学。该项目的预期结果将是选择最合适的“开发候选药物”，该药物将立即准备好进行IND提交的确定性GLP毒理学研究，并作为戒烟药物治疗。