PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

描述(由申请人提供)：拟议的第二阶段SBIR的目标是推动一类新的α3β4尼古丁乙酰胆碱受体拮抗剂(新分子实体)，它们在体内显示出良好的阻断尼古丁自我给药和恢复尼古丁寻求的效果，并发展为戒烟疗法。我们已经发现了一系列高效的α3β4 nAChR功能拮抗剂，它们都具有个位数的纳摩尔结合亲和力和100倍于密切相关的42和7 nAChR亚型的靶点选择性。在我们成功的第一阶段努力中，我们表明这一系列的三种先导化合物不仅在低剂量下显著阻止大鼠尼古丁的自我给药，对食物反应没有影响，而且还阻止尼古丁寻求的恢复，这是一种复发的动物模型。这些选择性α3β4 nAChR配体的显著疗效强烈表明，α3β4 nAChR功能拮抗是戒烟药物治疗的一种有前途的药理机制。我们已经实现了第一阶段SBIR的所有目标，并进行了额外的研究，以支持这类化合物适用于进一步的药物开发。我们现在寻求第二阶段的支持，通过一系列的“降低风险”实验，推进一组优化的候选药物，目的是为建议的适应症(戒烟)选择一个“开发候选”。第二个目标是在我们的系列中至少定位一种其他化合物作为相同适应症的后备药物或作为其他适应症的未来开发候选药物。在目标1中，我们将扩大(非GMP)一组优化的Alpha3beta4nAChR配体，用于配方前和开发活动。在目标2中，将在一系列ADME研究和两个物种的PK中描述开发候选者的特征。在目标3中，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选定候选人的口服疗效。在目标4中，我们将开展详细的安全药理学和早期毒理学研究，包括GLP对狗的心血管安全性、功能观察电池和两个物种的测距毒理学。该项目的预期结果将是选择最合适的“开发候选者”，这将立即准备好为IND提交的最终GLP毒理学研究和作为戒烟药物治疗的进展。

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.