Topical selective T-type blockers for the treatment of pruritus

局部选择性 T 型阻滞剂治疗瘙痒

基本信息

批准号：
9907737
负责人：
Fanny Astruc Diaz
金额：
$ 22.5万
依托单位：
DERMAXON, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907737
关键词：
3-Dimensional Action Potentials Acute Address Adult Adverse effects Affect American Anti-inflammatory Antipruritic Effect Antipruritics Autoimmune Responses Behavior Blood Circulation C Fiber CD4 Positive T Lymphocytes Calcium Calcium Channel Blockers Cardiotoxicity Cells Chemicals Clinical Research Cytochromes Data Dermatologic Dermatology Development Disease Dose Esthesia Exhibits Experimental Autoimmune Encephalomyelitis Family Fire - disasters Functional disorder Goals Health Hidradenitis Suppurativa Histamine Human Human Genome Immune Immunology In Vitro Inflammation Inflammatory Investigational New Drug Application Lead Legal patent Light Liver Mechanoreceptors Mediating Metabolic Metabolism Microsomes Modeling Mus Names Nerve Nerve Endings Neurons Nitrogen Nociception Oral Administration Patients Pattern Perception Peripheral Peripheral Blood Mononuclear Cell Permeability Pharmaceutical Chemistry Pharmacology Phase Production Property Protein Isoforms Prurigo Pruritus Resistance Risk Rodent Role Safety Shapes Skin Small Business Innovation Research Grant Stimulus Structure Symptoms Synapses T-Lymphocyte T-Type Calcium Channels TNF gene Therapeutic Time Topical application Touch sensation Toxic effect Work absorption analog associated symptom base chronic inflammatory skin chronic itch cytokine design improved in vivo in vivo Model inhibitor/antagonist keratinocyte differentiation macrophage next generation novel novel therapeutics off-patent pediatric patients pre-clinical preclinical study public health relevance response skin disorder

项目摘要

Project Summary / Abstract: Pruritus, also called itch, is the most frequent dermatological symptom in the US with up to 20% of Americans being affected. Pruritic stimuli are detected by a subset of nociceptive neurons, pruriceptors, which fire action potential in response to peripheral activation by TH2 or TH17 molecules induced by chronic inflammatory skin diseases such as ichthyosis, prurigo nodularis, and hidradenitis suppurativa. T-type calcium channels contribute to the firing behavior of itch-sensing neurons in synaptic skin nerve terminals and have recently been discovered to mediate calcium entry in immune cells. This T-type calcium channel expression pattern is consistent with their critical roles at detecting itch sensations associated with skin inflammatory diseases. Preliminary work has enabled us to formulate the central hypothesis that topical inhibition of the three T-type channel isoforms in the skin will silence action potential (AP) discharge of itch Aδ and C-fibers induced by pruritogenic and inflammatory cytokines, will directly reduce the release of these cytokines by TH2 or TH17 cells, and will lead to improved efficacy and limited systemic exposure, together reducing the risk of adverse effects compared to systemic treatments. Our hypothesis is strongly supported by our experimental findings. First, our lead compound, DX416, is a potent inhibitor of the three T-type channels, Cav3.1, Cav3.2, and Cav3.3 at sub-micromolar levels. Second, treatment with DX416 does not induce psychoactivity in rodents but profoundly reduces histamine-evoked itch in mice after intradermal administration. Third, we discovered DX401, a T-type blocker that reduces histamine-evoked itch after oral administration. Fourth, we show for the first time that these two Cav3s blockers, DX416 and DX401, significantly reduce the release of TH2 pruritic cytokine, IL- 31, after human peripheral blood mononuclear cell (PBMC) activation, and TH17-synergizing cytokine, TNFα, by activated macrophages. The overall goal of this collaborative effort between DermaXon’s experts in medicinal chemistry, immunology, and dermatology is to demonstrate the technical feasibility of developing inhibitors of skin T-type channels as novel therapeutics for the topical treatment of pruritus associated with inflammatory skin diseases. Our objectives in this proposal are: Aim 1) complete the optimization of our first topical T-type lead inhibitor DX416, based on our previously designed chemotypes and characterize their Cav3s activity and selectivity; Aim 2) compare the effect of four Cav3s blockers selected in SA1 on proinflammatory and pruritogenic cytokine release by activated immune cells, and assess their safety; Aim 3) compare the anti-pruritic efficacy after intra-dermal administration of two T-type channels inhibitors selected in Aim 2 using the histamine- evoked acute itch and the dry skin chronic itch in vivo models. The identification of lead compounds that are active in preclinical acute and chronic itch models will set the stage for a next generation of topical pruritus therapeutics to be used in both adult and pediatric patients suffering from itch associated with inflammatory skin diseases, and will support development of a novel therapeutic topical treatment.

项目摘要/摘要：瘙痒症，也称为瘙痒，是美国最常见的皮肤病症状多达 20% 的美国人受到伤害性神经元子集的检测，瘙痒感受器，响应 TH2 或 TH17 分子诱导的外周激活而激发动作电位慢性炎症性皮肤病，如鱼鳞病、结节性痒疹和 T 型化脓性汗腺炎。钙通道有助于突触皮肤神经末梢中瘙痒敏感神经元的放电行为最近发现这种 T 型钙通道表达可介导钙进入免疫细胞。模式与它们在检测与皮肤炎症相关的瘙痒感方面的关键作用一致初步工作使我们能够提出中心假设，即局部抑制这三种疾病。皮肤中的 T 型通道异构体将抑制痒 Aδ 和 C 纤维引起的动作电位 (AP) 放电通过致痒和炎症细胞因子，将直接减少 TH2 或 TH17 释放这些细胞因子细胞，并将导致功效提高和全身暴露有限，同时降低不良风险与全身治疗相比，我们的假设得到了实验结果的有力支持。首先，我们的先导化合物 DX416 是三种 T 型通道 Cav3.1、Cav3.2 和 Cav3.3 的有效抑制剂其次，DX416 治疗不会引起啮齿类动物的精神活动，但会引起精神活动。皮内给药后可显着减少组胺引起的瘙痒第三，我们发现了 DX401，一种 T 型阻滞剂，可减少口服后组胺引起的瘙痒第四，我们首次展示。这两种 Cav3s 阻滞剂 DX416 和 DX401 显着减少 TH2 瘙痒细胞因子 IL- 的释放 31，人外周血单核细胞（PBMC）激活后，TH17协同细胞因子TNFα通过激活巨噬细胞是 DermaXon 医学专家之间合作的总体目标。化学、免疫学和皮肤病学的目的是证明开发抑制剂的技术可行性皮肤 T 型通道作为局部治疗与炎症性皮肤相关的瘙痒的新疗法我们在该提案中的目标是：目标 1) 完成我们第一个局部 T 型引线的优化。抑制剂 DX416，基于我们之前设计的化学型并表征其 Cav3s 活性和选择性；目标 2) 比较 SA1 中选择的四种 Cav3s 阻滞剂对促炎和目的3）比较激活的免疫细胞释放的致痒细胞因子，并评估其安全性；使用组胺-在目标 2 中选择的两种 T 型通道抑制剂进行皮内给药后的功效诱发急性瘙痒和干性皮肤慢性瘙痒的体内模型中的先导化合物的鉴定。活跃于临床前急性和慢性瘙痒模型将为下一代局部瘙痒奠定基础用于患有与炎症性皮肤相关的瘙痒的成人和儿童患者的治疗方法疾病，并将支持新型治疗性局部治疗的开发。