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.

项目概要/摘要 DermaXon 的项目目标是开发有效的、基于底物的选择性 CYP26 抑制剂（酶） 负责表皮中全反式视黄酸（atRA）的代谢，作为口服治疗严重 顽固性痤疮。这种方法将提供改进的痤疮治疗方法，且不会产生副作用 与目前市售的类视黄醇有关。这也可以避免潜在的不利影响。 先前研究的含唑 CYP26 抑制剂观察到脱靶细胞色素 P450 (CYP) 抑制 如利阿唑。痤疮影响超过 4000 万美国人，每年造成的损失超过 30 亿美元，并且 对生活质量产生重大负面影响。痤疮患者已被证明具有社交、 心理和情绪困扰与癫痫和糖尿病患者相似。类维生素A，一种 一类 atRA 相关化合物，具有溶解粉刺和抗炎特性。然而， 相当大的不良反应，包括红斑、瘙痒、干燥、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 亚型 CYP26A1 和 CYP26B1 介导。目前已获批准 局部类视黄醇靶向直接激活视黄酸受体，也是 CYP26A1 的有效抑制剂 和 B1，这可能解释了它们与类维生素A通路过度刺激相关的不良副作用。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) 是特异性 CYP26 抑制剂，不与核受体和脱靶 CYP 相互作用，b) 增强 纳摩尔浓度的 atRA 对重建的人表皮的影响，c) 不具有遗传毒性， 心脏毒性或刺激性，d) 具有体内粉刺溶解功效，e) 可口服生物利用，f) 可制造。 目标 1 的研究重点是完成这些化合物的口腔表征及其生物分布 皮肤和体内血浆中。目标 2 的研究将重点关注犀牛小鼠的口服剂量范围功效研究。 在目标 3 中，我们将确定所选抑制剂在活性剂量下的胚胎-胎儿发育毒性。经过 在该项目结束时，DermaXon 将确定一种口服 CYP26，为 IND 启用研究做好准备，解决以下问题 严重痤疮患者的治疗需求。