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.

项目概要/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。瘙痒刺激由伤害感受神经元的子集检测， 免疫感受器，其响应于由TH 2或TH 17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、结节性湿疹和化脓性汗腺炎。t型 钙通道有助于突触皮肤神经末梢中的痒感神经元的放电行为， 最近发现其介导免疫细胞中的钙进入。这种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中的关键作用一致 疾病初步的工作使我们能够制定的中心假设，局部抑制的三个 皮肤中的T型通道亚型将使瘙痒Aδ和C纤维诱导的动作电位（AP）放电沉默 通过促炎性和炎性细胞因子，将直接减少TH 2或TH 17释放这些细胞因子 细胞，并将导致改善的疗效和有限的全身暴露，共同降低不良反应的风险， 与全身性治疗相比。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DX 416是三种T型通道Cav3.1、Cav3.2和Cav3.3的有效抑制剂 在亚微摩尔水平上。其次，用DX 416治疗不会诱导啮齿动物的精神活动， 在皮内给药后显著降低小鼠中组胺诱发的瘙痒。第三，我们发现了DX 401， 一种T型阻滞剂，口服后可减少组胺引起的瘙痒。第四，我们首次展示 这两种Cav 3s阻断剂DX 416和DX 401显著减少了TH 2炎性细胞因子IL-1的释放。 31，在人外周血单核细胞（PBMC）活化和TH 17协同细胞因子TNFα后， 激活的巨噬细胞DermaXon的医学专家之间合作的总体目标是 化学，免疫学和皮肤病学的研究是为了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症的新疗法 疾病我们的目标是：目标1）完成我们的第一个局部T型电极导线的优化 抑制剂DX 416，基于我们先前设计的化学型并表征其Cav 3s活性， 选择性;目的2）比较在SA 1中选择的四种Cav 3s阻断剂对促炎性和 通过激活的免疫细胞释放促炎性细胞因子，并评估其安全性;目的3）比较 使用组胺皮内给药目标2中选择的两种T-型通道抑制剂后的功效- 诱发急性瘙痒和干性皮肤慢性瘙痒的体内模型。确定的铅化合物， 在临床前急性和慢性瘙痒模型中的活性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剂 疾病，并将支持一种新的治疗局部治疗的发展。