Targeting TRP channels for novel topical treatment of atopic dermatitis

摘要 我们已经开发出了TB16-8，这是一种对TRPV4和TRPA1离子都有有效抑制作用的小分子 频道。这两种离子通道与特应性皮炎(特应性皮炎)及其主要临床症状有关 标志性、慢性和衰弱的瘙痒(瘙痒)。我们已经证明了局部应用在Low 微克量的这种化合物有效地抑制小鼠和猪的瘙痒和炎症-用作 动物模型-治疗特应性皮肤病的各种症状。 目前已经批准了治疗特应性皮肤病及其症状的方法；然而，没有一种药物是通用的。 并不是所有的特应性皮肤药物都适合所有的患者。TB16-8是一种单一的治疗方法，应用 局部地，潜在地取代免疫调节药物，或作为对当前治疗的补充 降低应用剂量的前景。TB16-8用于局部应用；因此，除了 为了提供短期缓解，目标是长期长期使用，而不良反应最小或没有 效果。 在目前的第一阶段提案中，我们将进行旨在将TB16-8定位为前IND状态的研究。首先，一个 将实现最优化的化学合成。合成过程的每一步都将经过仔细的分析 并经过优化以生产满足FDA和ICH GMP要求的最终药物产品。的影响 在接触性皮炎的小鼠临床前模型中，将通过DNFB(2，4-DNFB)致敏来研究TB16-8。 使用基于丙酮-二乙基的干燥皮肤模型进行慢性瘙痒性皮炎的研究 乙醚。将测量抓挠行为和皮肤炎症。皮肤炎及其生物分布 还将对猪血液和体表中的TB16-8进行评估。 我们的初步数据很强，可能会被认为我们的产品应该被考虑直接 第二阶段；然而，局部用药后皮肤浓度和体循环中TB16-8的检测 猪体内给药，一个与人类局部给药相关的模型，还没有收集到，使得 这一第一阶段是达到IND前状态之前的一个必要阶段。我们将补充安全和长达48小时 目前在两种动物模型中可以获得TB16-8的生物分布数据，我们将优化化学物质 TB16-8的合成 在这些研究之后，将进行第二阶段的应用，在该阶段中，IND要求进行诸如眼睛刺激等研究 将进行分析、毒理学和其他相关研究。这些未来的研究将提供必要的数据 与FDA会面并讨论为局部治疗特应性疾病定位TB16-8所需的实验 德姆。

SUMMARY We have developed TB16-8, a small molecule that is an effective inhibitor of both TRPV4 and TRPA1 ion channels. These two ion channels are associated with atopic dermatitis (Atopic Derm) and its dominating clinical hallmark, chronic and debilitating pruritus (itch). We have demonstrated that the topical application at low microgram amounts of this compound effectively inhibits itch and inflammation in mice and swine—used as animal models—for various symptoms of Atopic Derm. Currently there are treatments approved for Atopic Derm and its symptoms; however, none is a universal drug, and not all Atopic Derm drugs are appropriate for all the patients. TB16-8 is intended as a single therapy, applied topically, potentially replacing immunomodulatory drugs, or as a complement for current treatments with a perspective of lowering applied doses. TB16-8 is intended for topical application; therefore, in addition to providing short term relief, an objective is chronic use for extended periods of time with minimal or no adverse effects. In the present Phase I proposal we will perform studies intended to position TB16-8 in pre-IND status. First, an optimized chemical synthesis will be achieved. Every step of the synthesis process will be carefully analyzed and optimized to generate a final drug product that satisfies FDA and ICH GMP requirements. The effect of TB16-8 will be studied in mouse preclinical models for contact dermatitis by sensitizing them with DNFB (2,4- dinitrofluorobenzene) and by chronic pruritogenic dermatitis using a dry skin model based on acetone-diethyl ether. Scratching behavior and skin inflammation will be measured. Skin inflammation and biodistribution of TB16-8 in the blood and integument of swine will also be evaluated. Our preliminary data are strong and could be perceived as if our product ought to be considered for a Direct to Phase II; however, dermal concentrations and detection of TB16-8 in the systemic circulation following topical administration in swine, a relevant model for topical administration in humans, have not been collected, making this Phase I a necessary stage prior to reaching pre-IND status. We will complement the safety and up to 48h biodistribution data of TB16-8 currently available in two animal models, and we will optimize the chemical synthesis of TB16-8. These studies will be followed by a Phase II application in which IND-required studies such as eye-irritation analysis, toxicology, and other relevant studies will be performed. These future studies will provide data required to meet with the FDA and discuss the necessary experiments to position TB16-8 for a topical treatment of Atopic Derm.