Targeting TRP channels for novel topical treatment of atopic dermatitis

靶向 TRP 通道用于特应性皮炎的新型局部治疗

• 批准号: 10005547
• 负责人: George Walter Koszalka
• 金额: $ 30.23万
• 依托单位: TRPBLUE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005547
• 关键词: Accounting; Acetone; Address; Adult; Adverse effects; Affect; Allergens; Allergic inflammation; Animal Model; Antipruritics; Atopic Dermatitis; Attenuated; Automobile Driving; Behavior; Benchmarking; Biodistribution; Blood; Blood Circulation; Blood specimen; Child; Chronic; Clinical; Complement; Contact Dermatitis; Country; Data; Dermal; Dermatitis; Detection; Development; Dinitrofluorobenzene; Disease Management; Disease remission; Dose; Drug Kinetics; Dryness; Environment; Ethyl Ether; Exanthema; Eye; Family suidae; Financial Hardship; Formulation; Future; Histamine; Histology; Human; Immune system; Immunomodulators; Inflammation; Inflammatory; Integumentary system; Ion Channel; Joints; Limb structure; Measures; Metabolism; Modeling; Molecular; Mus; Neck; Pain; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Positioning Attribute; Pre-Clinical Model; Preparation; Prevalence; Process; Production; Property; Protocols documentation; Pruritus; Punch Biopsy; Quality of life; Records; Redness; Relapse; Risk; Role; Safety; Scientist; Series; Serotonin; Side; Signal Transduction; Skin; Stimulus; Swelling; Symptoms; TRP channel; Testing; Therapeutic; Time; Topical application; Toxicology; Work; absorption; base; chemical synthesis; chronic itch; cost; design; drug metabolism; effective therapy; experimental study; improved; in vivo; inhibitor/antagonist; intradermal injection; irritation; liquid chromatography mass spectrometry; molecular marker; mouse model; neurosensory; novel; novel therapeutics; pre-clinical; reduce symptoms; response; side effect; skin disorder; skin irritation; small molecule; tissue injury

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.

概括 我们已经开发了TB16-8，这是一种小分子，是TRPV4和TRPA1离子的有效抑制剂 频道。这两个离子通道与特应性皮炎（特应性皮肤）及其主导的临床有关 Hallmark，长期和衰弱的瘙痒（瘙痒）。我们已经证明了低点的局部应用 微克量的该化合物有效地抑制了小鼠和猪的瘙痒和感染 - 动物模型 - 特应性皮肤的各种符号。 目前，有批准特应性皮肤及其症状的治疗方法。但是，没有一个是普遍的药物， 并非所有特应性皮肤药物都适合所有患者。 TB16-8旨在用于应用 局部地，有可能替代免疫调节药物，或作为目前治疗的完成 降低施用剂量的观点。 TB16-8用于局部应用；因此，除了 提供短期救济，目标是长期使用的长期使用，而逆境很少或没有逆境 效果。 在目前的I阶段，我们将进行旨在将TB16-8定位为预定状态的研究。首先，一个 将实现优化的化学合成。综合过程的每个步骤都将仔细分析 并进行了优化，以生成满足FDA和ICH GMP要求的最终药物。效果 TB16-8将通过用DNFB敏感（2,4--- 使用基于丙酮二甲基的干燥皮肤模型，二硝基氟苯和通过慢性核性皮炎 醚。将测量刮擦行为和皮肤感染。皮肤注射和生物分布 还将评估猪的血液和指数中的TB16-8。 我们的初步数据很强，可以被认为是直接考虑我们的产品 第二阶段；但是，局部局部循环中的皮肤浓度和TB16-8的检测 尚未收集猪的管理，这是人类局部管理的相关模型，使得 这阶段I在达到预先身份之前的必要阶段。我们将完成安全性，最多48h TB16-8的生物分布数据目前在两种动物模型中可用，我们将优化化学物质 TB16-8的合成。 这些研究将随后进行II期应用，在该应用中，诸如眼部骚扰之类的指定研究 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所需的数据 与FDA会面并讨论必要的实验，以将TB16-8定位用于特应当的局部处理 真皮。