Topical selective T-type blockers for the treatment of pruritus

局部选择性 T 型阻滞剂治疗瘙痒

• 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
• 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

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，也称为瘙痒，是美国最常见的皮肤病症状 多达20％的美国人受到影响。脑刺刺激由伤害性神经元的子集检测到 Pruceptors，Th2或Th17分子诱导的外围激活响应的发射动作潜力 通过慢性炎症性皮肤疾病，例如鱼质病，prurigo nodularis和Hidradenenitis suppurativa。 T型 钙通道有助于突触皮肤神经末端瘙痒性神经元的发射行为， 最近发现了介导免疫细胞中的钙进入。此T型钙通道表达 模式与它们在检测与皮肤炎症相关的瘙痒感觉方面的关键作用一致 疾病。初步工作使我们能够提出一个中心假设，即局部抑制三个 皮肤中的T型通道同工型将使瘙痒Aδ和C纤维诱导的动作电位（AP）排放 通过瘙痒和炎症细胞因子，将直接减少Th2或Th17的这些细胞因子的释放 细胞，并将导致提高效率和有限的全身暴露，一起降低了广告的风险 与全身治疗相比的影响。我们的实验发现支持我们的假设。 首先，我们的铅化合物DX416是三个T型通道的潜在抑制剂Cav3.1，Cav3.2和Cav3.3。 在亚微摩尔水平上。其次，用DX416治疗不会诱导啮齿动物的心理活性，而是 严重减少皮内给药后小鼠的组胺引起的瘙痒。第三，我们发现了DX401， 口服给药后减少组胺引起的瘙痒的T型阻滞剂。第四，我们第一次展示 这两个Cav3s阻滞剂DX416和DX401显着降低了Th2 ruritic细胞因子的释放，IL- 31，在人类外周血单核细胞（PBMC）激活和Th17-柔肌细胞因子TNFα之后，通过 活化的巨噬细胞。 Dermaxon的医学专家之间的合作努力的总体目标是 化学，免疫学和皮肤病是为了证明开发抑制剂的技术可行性 皮肤T型通道作为与炎性皮肤相关的瘙痒局部治疗的新型疗法 疾病。本提案中我们的目标是：目标1）完成我们第一个局部T型铅的优化 抑制剂DX416，基于我们先前设计的化学型，并表征其CAV3S活性和 选择性；目标2）比较SA1中选择的四个CAV3S阻滞剂对促炎和 通过活化的免疫细胞释放瘙痒性细胞因子，并评估其安全性；目标3）比较反pr术 使用组胺 - 在AIM 2中选择两个T型通道抑制剂后，使用组胺 - 诱发的急性瘙痒和干燥的皮肤慢性瘙痒在体内模型中。识别铅化合物 活跃于临床前急性和慢性瘙痒模型将为下一代瘙痒奠定阶段 用于与炎症皮肤相关的成人和儿科患者使用的治疗 疾病，并将支持一种新型治疗局部治疗的发展。