Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation

 描述（由申请人提供）：吸烟仍然是美国头号可避免的死亡原因，每年花费数百亿美元。目前的治疗包括用贴剂或口香糖替代尼古丁，用安非他酮抑制多巴胺系统，以及用伐尼克兰部分激活N442神经元烟碱乙酰胆碱受体（nAChR）。这些药物在最初使用时都不是特别有效，即使在最初成功的情况下，无论治疗药物或疗法如何，复发率也接近80%。临床试验中的其他疗法包括非选择性nAChR拮抗剂美加明、尼古丁抗体和行为矫正。与香烟成瘾性最密切相关的nAChR是nAChR。thi受体的激活被认为是尼古丁奖赏的主要介质，并且选择性但低亲和力的β 4 β 2 nAChR拮抗剂DH β E已被证明在啮齿动物模型中阻断尼古丁自我给药。然而，很少有高亲和力和选择性的β 4 β 2拮抗剂可作为戒烟药物进行研究。从一个包含超过500万个单独化合物的小分子组合库开始，我们已经确定了选择性nAChR化合物。在我们的I期申请的资助下，我们已经确定了具有非常高的亲和力、效力和选择性的先导化合物，无论是在结合亲和力还是在体外功能活性方面，都是在nAChR上。这两种化合物都是104 - 102 nAChR的完全拮抗剂。已证明一种化合物可减弱大鼠的尼古丁自我给药和复吸。在这个II期SBIR中，我们建议优化我们的先导化合物，以进一步改善药物样性质，同时保持或提高亲和力和选择性。在特定目标1中，类似于传统的药物发现“命中-先导”过程，将进行额外的SAR以改善我们当前先导化合物的PK/PD特性。这一目标将包括药物化学，并结合体外亲和力和功效测试，沿着药理学分析，以识别药物样化合物。具体目标2将类似于药物发现中的“导致开发”过程，其中将在一系列体外和体内试验中测试选定的高亲和力和选择性拮抗剂，以确定口服生物利用度、稳定性、血脑屏障渗透、药代动力学和hERG抑制。除了确定阻断大鼠尼古丁自我给药和恢复能力的体内疗效外，该目的还将包括确定对运动、焦虑、抑郁和奖赏/厌恶的其他药理学作用，以选择化合物以推进未来IND使能毒理学。

 DESCRIPTION (provided by applicant): Smoking remains the number one avoidable cause of death in the United States and costs the economy tens of billions of dollars every year. Current therapies include nicotine replacement with a patch or gum, inhibition of the dopamine system with bupropion, and partial activation of the 42 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline. None of these have been particularly effective upon initial use, and even in the cases of initial success relapse rates are nearly 80% regardless of the treatment drugs or therapies. Additional therapies in clinical trials include the non-selective nAChR antagonist mecamylamine, nicotine antibodies, and behavior modification. The nAChR most closely associated with the addictive nature of cigarettes is the 42 nAChR. Activation of thi receptor is considered to be the primary mediator of nicotine reward and the selective but low affinity 42 nAChR antagonist DHE has been demonstrated to block nicotine self-administration in rodent models. However, there are very few high affinity and selective 42 antagonists available to examine as smoking cessation medications. Starting from a small molecule combinatorial library containing more than 5 million individual compounds, we have identified selective nAChR compounds. With funding from our Phase I application we have identified lead compounds with very high affinity, potency and selectivity, both with respect to binding affinity and in vitro functional activity, at the 42 nAChR. Both of these compounds ae full antagonists at 42 nAChRs. One compound has been demonstrated to attenuate nicotine self-administration and reinstatement in rats. In this Phase II SBIR, we propose to optimize our lead compounds to further improve drug-like properties, while maintaining or improving affinity and selectivity. In Specific Aim 1, similar to a traditional drug discovery "hit-to-lead" process, additional SAR will be conducted to improve the PK/PD properties of our current lead compounds. This aim will include medicinal chemistry and coupled with in vitro affinity and efficacy testing along with the pharmacological profiling to identify drug-like compounds. Specific Aim 2 will be similar to the "lead to development" process within drug discovery, in which selected high affinity and selective antagonists will be tested in a battery of in vitro and n vivo assays to determine oral bioavailability, stability, blood brain barrier penetration, pharmacokinetics, and hERG inhibition. In addition to determining in vivo efficacy for ability to block nicotine self-administration and reinstatement in rats, this aim will include the determination of additional pharmacological effects on locomotion, anxiety, depression, and reward/aversion, in order to choose compounds to move forward to future IND-enabling toxicology.