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.

项目总结/摘要 DermaXon的项目目标是开发有效的、基于底物的、选择性的CYP 26抑制剂， 负责表皮中全反式视黄酸（atRA）的代谢，作为重度 令人沮丧的痤疮。这种方法将提供一种改进的痤疮治疗没有不利影响 与目前市售的类维生素A有关。这也将避免由 使用先前研究的含唑类CYP 26抑制剂观察到的脱靶细胞色素P450（CYP）抑制 例如利阿唑。痤疮影响超过4000万美国人，每年花费超过30亿美元， 对生活质量产生重大负面影响。痤疮患者已经被证明会经历一定程度的社会， 心理和情绪困扰类似于癫痫和糖尿病患者报告的情况。类维生素A a 类atRA相关化合物，具有comedolytic和抗炎性质。然而，在这方面， 相当多的不良反应，包括红斑、瘙痒、干燥和脱皮，以及全身不良反应。 对皮肤粘膜、肌肉骨骼和眼科系统的影响是限制因素。atRA的清除率 皮肤主要由CYP家族26同种型CYP 26 A1和CYP 26 B1介导。目前批准 靶向直接激活视黄酸受体的外用类维生素A，也是CYP 26 A1和CYP 26 A2的强效抑制剂。 和B1，这可能解释了它们与类维生素A通路过度刺激有关的不良副作用。我们有 CYP 26 A1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）是不与核受体和脱靶CYP相互作用的特异性CYP 26抑制剂，B）增强 纳摩尔浓度的atRA在重建的人表皮中的作用，c）不是遗传毒性的， 心脏毒性或刺激性，d）在体内表现出溶瘤功效，e）是口服生物可利用的，和f）是可制造的。 目标1中的研究重点是完成这些化合物的口服表征及其生物分布 在皮肤和体内血浆中。目标2中的研究将侧重于在犀牛小鼠中进行的经口剂量范围有效性研究。 在目标3中，我们将确定活性剂量下选定抑制剂的胚胎-胎仔发育毒性。通过 本项目结束时，DermaXon将确定一种口服CYP 26，可用于IND启动研究， 严重痤疮患者的治疗需求。