A2a Adenosine Blockers for Parkinson's Disease

A2a 腺苷阻滞剂治疗帕金森病

• 批准号: 6882125
• 负责人: ROBERT D THOMPSON
• 金额: $ 13.92万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882125
• 关键词: 6 hydroxydopamine; Parkinson' s disease; adenosine; autoradiography; brain disorder chemotherapy; combination chemotherapy; disease /disorder model; drug design /synthesis /production; drug interactions; drug screening /evaluation; high performance liquid chromatography; immunocytochemistry; laboratory mouse; levodopa; methylphenyltetrahydropyridine; neurotransmitter antagonist; nonhuman therapy evaluation; psychomotor function; radioimmunoassay

DESCRIPTION (PROVIDED BY APPLICANT): Selective antagonists of A2A adenosine receptors have proven to be effective for the treatment of Parkinson's disease (PD) both in animal models and in a human trial. However, the initial clinical trial was stopped in phase 3 due to detection of animal toxicity of KW6002. Other investigational compounds lack sufficient potency, selectivity or bioavailability to be considered clinical candidates. This proposal is a phase I SBIR to investigate proprietary novel potent, selective and bioavailable AM blockers for the treatment of PD. It is collaboration between Adenosine Therapeutics, LLC, where medicinal chemistry and compound characterization are conducted, and the Boston University laboratory of Dr. Jiang-Fan Chen, where compounds are investigated in several mouse models of PD. We have already identified one compound, ATL-444, that is very effective in stimulating locomotor activity in a mouse model that is highly predictive of efficacy in PD. There are two specific aims: Aim 1 - Identify another compound, in addition to ATL-444, that is a therapeutic candidate for PD. For this aim, additional compounds will be synthesized and screened, first in radioligand binding assays, and subsequently for locomotor activity in mice. ATL-444 and 1 additional compound will be selected for detailed evaluation in aim 2. Aim 2- Evaluate novel A2A antagonists in four mouse models of PD. These include: A) motor function in normal and dopamine-depleted mice; B) synergistic activity with L-dopa to stimulate motor activity in dopamine-depleted mice; C) attenuation MPTP-induced neurotoxicity by inhibiting MPTP metabolism; and D) delayed L-dopa-induced locomotor sensitization in unilateral 6-OHDA-lesioned mice. We anticipate that we will identify 1 or 2 new clinical candidates for the treatment of PD. Our long-term goal is to bring a new compound into clinical trials. Such a new compound has high therapeutic significance and would be of high commercial value.

描述（由申请人提供）：在动物模型和人类试验中，A2A腺苷受体的选择性拮抗剂已被证明对帕金森氏病（PD）的治疗有效。但是，由于发现KW6002的动物毒性，因此在第3阶段停止了最初的临床试验。其他研究化合物缺乏足够的效力，选择性或生物利用度，无法被视为临床候选者。该提案是研究专有的新型有效，选择性和生物利用AM阻滞剂的I阶段SBIR，用于治疗PD。它是进行药物化学和复合表征的腺苷治疗学有限责任公司与江云陈的波士顿大学实验室之间的合作，其中在几种PD小鼠模型中研究了化合物。我们已经确定了一种化合物ATL-444，该化合物在高度预测PD功效的小鼠模型中刺激运动活性非常有效。有两个具体的目标： AIM 1-除了ATL -444之外，还确定另一种化合物，即PD的治疗候选者。为此，将合成和筛选其他化合物，首先在放射性结合测定中，然后在小鼠中进行运动活性。将选择ATL-444和1个附加化合物以在AIM 2中进行详细评估。 AIM 2-在四种PD小鼠模型中评估新型A2A拮抗剂。其中包括：a）正常和多巴胺耗尽小鼠中的运动功能； b）与L-DOPA的协同活性，可刺激多巴胺缺失小鼠的运动活性； c）通过抑制MPTP代谢，衰减MPTP诱导的神经毒性； d）在单侧6-OHDA渗透的小鼠中延迟L-DOPA诱导的运动敏化。 我们预计我们将确定1或2个新的临床候选PD治疗。我们的长期目标是将新化合物带入临床试验中。这种新化合物具有很高的治疗意义，并且具有很高的商业价值。