A novel class of anti-acne therapeutics

寻常痤疮是一种常见的皮肤病，影响80%的人口，通常是青少年和年轻人 成年人。美国有超过5000万人受到痤疮的影响，这是一个价值20亿美元的痤疮市场 治疗，其中80%来自处方药。尽管粉刺不会危及生命 它仍然有很高的心理社会影响，导致抑郁、焦虑、愤怒、自杀念头、 身体上的伤疤和生活质量的下降。粉刺的主要原因是皮脂过度分泌。 皮脂腺，毛囊上皮过度角化，痤疮假单胞菌增殖和炎症。 不幸的是，皮脂调节的分子机制还不清楚，这阻碍了 安全有效的皮脂抑制疗法的产生。维甲酸已经被使用了20多年了 治疗严重痤疮已有数年的时间，是唯一被批准对多种病理性疾病有效的疗法 粉刺的过程。然而，由于对维甲酸致畸特性的严重担忧， 它们的使用现在是FDA强制注册计划的一部分。此外，异维A酸与严重的 副作用包括临床抑郁、炎症性肠病和敏感皮肤。显然有必要 用于针对皮脂细胞产生皮脂的安全有效的治疗。在第一阶段研究中，我们筛选了 在抑制皮脂细胞的过氧化物酶体生物发生表型筛选中鉴定的一类新化合物 脂类生物合成。我们成功地鉴定了活性分子，建立了初步的构效关系 在动物模型中展示了与异维A酸相当的体内疗效 关于皮脂生成的。在这个第二阶段的应用中，我们将使用药物化学方法来扩展这一系列 利用我们的皮脂细胞筛选平台和体内模型鉴定多种新的口腔化合物 用于铅优化的生物可用小分子。使用这种方法，我们的目标是提供安全、有效的 治疗寻常痤疮的皮脂抑制剂。

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.