Selective CYP26 inhibitors for the oral treatment of recalcitrant nodular acne.

用于口服治疗顽固性结节性痤疮的选择性 CYP26 抑制剂。

• 批准号: 10822482
• 负责人: Philippe J Diaz
• 金额: $ 29.54万
• 依托单位: DERMAXON, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822482
• 关键词: Acetone; Acne; Active Sites; Address; Adverse effects; Affect; American; Anti-Inflammatory Agents; Azoles; Binding; Biodistribution; Biological Availability; CYP26B1 gene; Calibration; Cardiotoxicity; Chemicals; Congenital ichthyosis; Cytochrome P450; Data; Detection; Dose; Drug Interactions; Dryness; Embryonic and Fetal Development; Enzymes; Epidermis; Epilepsy; Erythema; Exhibits; FDA approved; Family; Fetus; Goals; Heme; Heme Iron; Human; Hypervitaminosis A; In Vitro; Inflammation; Irritants; Isotretinoin; Journals; Legal patent; Liarozole; Marketing; Mediating; Metabolism; Miniature Swine; Morphology; Mus; Musculoskeletal; Nitrogen; Nuclear Receptors; Oral; Oral Administration; Oral Characters; Pathway interactions; Patients; Peer Review; Permeability; Pharmaceutical Preparations; Phase; Placenta; Plasma; Production; Property; Protein Isoforms; Pruritus; Publishing; Quality of life; Rattus; Reporting; Resistance; Retinoic Acid Receptor; Retinoids; Route; Sebum; Series; Skin; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Steroid biosynthesis; Structure; System; Therapeutic; Therapeutic Agents; Topical application; Toxic effect; Toxicokinetics; Tretinoin; analytical method; comparative efficacy; compliance behavior; cost; covalent bond; design; diabetic patient; efficacy study; emotional distress; experience; fetal; improved; in vivo; inhibitor; irritation; keratinization; keratinocyte; method development; nanomolar; novel; pharmacologic; psychological distress; public health relevance; reproductive toxicity; response; retinoic acid 4-hydroxylase; scaffold; side effect; skin disorder; skin irritation; social; timeline

Project Summary / Abstract DermaXon's project goal is to develop efficacious, substrate-based, selective inhibitors of CYP26s, the enzymes responsible for the metabolism of all-trans retinoic acid (atRA) in the epidermis, as an oral treatment for severe recalcitrant acne. This approach will provide an improved acne therapeutic without the adverse effects associated with currently marketed retinoids. This would also avoid the potential adverse effects caused by the off-target cytochrome P450 (CYP) inhibition seen with previously investigated azole-containing CYP26 inhibitors such as liarozole. Acne affects more than 40 million Americans, costs upwards of $3 billion annually, and has a significant negative impact on quality of life. Acne patients have been shown to experience levels of social, psychological and emotional distress similar to those reported in epileptic and diabetic patients. Retinoids, a class of atRA-related compounds, possess comedolytic and anti-inflammatory properties. However, considerable adverse effects including erythema, pruritus, dryness, and peeling, as well as systemic adverse effects on mucocutaneous, musculoskeletal, and ophthalmic systems, are limiting factors. Clearance of atRA in the skin is predominantly mediated by the CYP family 26 isoforms CYP26A1 and CYP26B1. Currently approved topical retinoids targeting direct activation of retinoic acid receptors, are also potent inhibitors of both CYP26A1 and B1, which likely explains their adverse side effects related to retinoid pathway overstimulation. We have potent and selective inhibitors of CYP26A1 and/or B1. Our preliminary data demonstrates that these inhibitors: a) are specific CYP26 inhibitor which do not interact with nuclear receptors and off-target CYPs, b) potentiates the effects of a nanomolar concentration of atRA in reconstructed human epidermis, c) are not genotoxic, cardiotoxic, or irritant, d) exhibits comedolytic efficacy in vivo e) are orally bioavailable and f) are manufacturable. The studies in Aim 1 focus on completing the oral characterization of these compounds and their biodistribution in skin and plasma in vivo. The studies in Aim 2 will focus on the oral dose range efficacy studies in rhino mice. In Aim 3, we will determine the embryo-fetal development toxicity of the selected inhibitor at the active dose. By the end of this project, DermaXon will have identified an oral CYP26 ready for IND-enabling studies addressing the therapeutic needs of severe acne patients.

项目摘要 /摘要 Dermaxon的项目目标是开发CYP26，酶的有效的，基于底物的选择性抑制剂 负责表皮中全反式视黄酸（ATRA）的代谢，作为严重的口服治疗 顽固的痤疮。这种方法将提供改进的痤疮治疗，而不会产生不良影响 与目前销售的类维生素相关。这也将避免由 先前研究的含硫烷的CYP26抑制剂，脱离靶向细胞色素P450（CYP）抑制 例如liarozole。痤疮会影响超过4000万美国人，每年成本超过30亿美元，并且有一个 对生活质量的重大负面影响。痤疮患者已被证明具有社交水平， 心理和情绪困扰类似于癫痫病和糖尿病患者报告的困扰。视网膜类动物，a 与ATRA相关的化合物类别具有喜剧和抗炎特性。然而， 相当多的不良反应，包括红斑，瘙痒，干燥和剥皮，以及全身性不良 对肌皮肤，肌肉骨骼和眼科系统的影响是限制因素。清除ATRA 皮肤主要由CYP家族26同工型CYP26A1和CYP26B1介导。目前已批准 靶向视黄酸受体直接激活的局部类视黄素也是两种CYP26A1的有效抑制剂 和B1，这可能解释了它们与维生素途径过度刺激有关的不良副作用。我们有 CYP26A1和/或B1的有效和选择性抑制剂。我们的初步数据表明这些抑制剂： a）是特定的CYP26抑制剂，不与核受体和脱靶CYP相互作用，b）增强剂 ATRA在重建的人表皮中的纳摩尔浓度的影响，c）不是遗传毒性的，不是遗传毒性 心脏毒性或刺激性d）在体内表现出喜剧效应e）是可生物利用的，f）可制造。 AIM 1中的研究专注于完成这些化合物的口头表征及其生物分布 在体内皮肤和血浆中。 AIM 2中的研究将重点放在犀牛小鼠的口服剂量范围疗效研究上。 在AIM 3中，我们将在活性剂量下确定所选抑制剂的胚胎发育毒性。经过 该项目的结束，Dermaxon将确定一个口头CYP26，准备用于解决方案的研究 严重痤疮患者的治疗需求。