A novel class of anti-acne therapeutics

一类新型抗痤疮疗法

• 批准号: 9789007
• 负责人: BENJAMIN M BUEHRER
• 金额: $ 74.52万
• 依托单位: VERGE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789007
• 关键词: Accure; Acne; Acne Vulgaris; Affect; Anger; Animal Model; Animals; Anxiety; Attention; Bioavailable; Biogenesis; Biological Assay; Biological Availability; Cells; Characteristics; Chemical Structure; Cicatrix; Clinical; Congenital Abnormality; Cremophor; Data; Dermal; Development; Epithelium; Exposure to; Feeling suicidal; Fibroblasts; Future; Generations; Goals; Hamsters; Human; Impairment; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intellectual Property; Isotretinoin; Laboratories; Lead; Life; Link; Lobule; Major Depressive Disorder; Mental Depression; Mesocricetus auratus; Modeling; Molecular; Oral; Organ; Organ Model; Pathologic Processes; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Population; Process; Production; Property; Propionibacterium acnes; Quality of life; Registries; Regulation; Retinoids; Sales; Sebaceous Glands; Sebum; Secure; Series; Skin; Structure-Activity Relationship; System; Teenagers; Teratogens; Testing; Therapeutic; Toxic effect; Water; aged; analog; appendage; base; clinical candidate; commercialization; cytotoxicity; genotoxicity; high resolution imaging; histological specimens; histological stains; in vivo; in vivo Model; inflammatory marker; inhibitor/antagonist; keratinocyte; lead optimization; lipid biosynthesis; new technology; novel; peroxisome; phase 1 study; pre-clinical; preclinical development; programs; psychosocial; safety testing; scaffold; screening; side effect; skin disorder; small molecule; therapeutic candidate; treatment group; young adult

Acne Vulgaris is a common skin disorder that affects 80% of the population, typically teenagers and young adults. Over 50 million people in the US are affected by acne generating a $2 billion market for acne treatments, 80% of which is derived from prescription medications. Although acne is not a life-threatening condition, it still has a high psychosocial impact resulting in depression, anxiety, anger, suicidal thoughts, physical scarring and decreased quality of life. The primary causes of acne are the overproduction of sebum by sebaceous glands, hyperkeratinization of follicular epithelium, P. acnes proliferation and inflammation. Unfortunately, the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics. Retinoids have been used for more than 20 years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne. However, because of serious concerns regarding the teratogenic properties of retinoids, their use is now part of an FDA-mandated registry program. In addition, isotretinoin has been linked to serious side effects including clinical depression, inflammatory bowel disease and sensitive skin. There is a clear need for safe and efficacious treatments that target sebum production in sebocytes. In Phase I studies we screened a novel class of compounds identified in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis. We successfully identified active molecules, developed initial structure activity relationship around a lead scaffold and demonstrated in vivo efficacy that is comparable to isotretinoin in an animal model of sebogenesis. In this Phase II application we will use a medicinal chemistry approach to expand this series of compounds using our sebocyte screening platform and in vivo models to identify multiple novel orally bioavailable small molecules for lead optimization. Using this approach, our goal is to deliver safe, effective sebum inhibitors for the treatment of acne vulgaris.

痤疮福音是一种常见的皮肤疾病，影响80％的人群，通常是青少年和年轻人 成年人。美国超过5000万人受痤疮的影响，产生了20亿美元的痤疮市场 治疗，其中80％来自处方药。虽然痤疮不是威胁生命的 条件，它仍然具有高的社会心理影响，导致抑郁，焦虑，愤怒，自杀思想， 身体疤痕和生活质量下降。痤疮的主要原因是皮脂生产过多 皮脂腺，卵泡上皮的过度分泌，痤疮P.增殖和炎症。 不幸的是，皮脂调节的分子机制尚不清楚，这已经阻碍了 生成安全有效的塞贝斯抑制剂。类维生素类似于20多个 多年治疗严重的痤疮，是唯一有效抗多重病理的批准疗法 痤疮的过程。但是，由于对类维生素类似的致畸特性的严重关注， 他们的使用现在是FDA规定的注册表程序的一部分。此外，异托诺二酸与严重有关 副作用，包括临床抑郁症，炎症性肠病和敏感皮肤。有明确的需求 对于靶向皮脂细胞生产皮脂细胞的安全有效的治疗方法。在第一阶段研究中，我们筛选了 在表型筛选中鉴定出过氧化物酶体生物发生的新型化合物，抑制皮脂细胞 脂质生物合成。我们成功鉴定了主动分子，发展了初始结构活性关系 围绕铅支架，并在动物模型中与异维诺蛋白相媲美的体内功效 皮脂发生。在此II阶段应用中，我们将使用药物化学方法来扩展这一系列 使用我们的皮脂细胞筛选平台和体内模型的化合物来识别多种新颖的口服 可生物利用的小分子用于铅优化。使用这种方法，我们的目标是提供安全，有效 皮脂抑制剂用于治疗痤疮的抑制剂。