A Soft Topical Antiandrogenic Drug

一种软性外用抗雄激素药物

• 批准号: 8588704
• 负责人: Wei-Chu Xu
• 金额: $ 23.74万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588704
• 关键词: Acids; Acne; Acne Vulgaris; Adverse effects; Affinity; Alopecia; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Animals; Antiandrogen Therapy; Aromatase; Bicalutamide; Binding; Biological Assay; Cell Culture Techniques; Cells; Development; Disease; Enzymes; Epidermis; Esters; Estradiol; Estrogens; Estrone; Evaluation; Family; Female; Finasteride; Flutamide; Gender; Goals; Hair; Hamsters; Hirsutism; Hormones; Human; Hydrolase; Hydrolysis; In Vitro; Ipsilateral; Laboratory Animals; Lead; Marketing; Medical; Metabolic; Methods; Nilutamide; Nuclear Receptors; Odds Ratio; Organ Size; Outcome; Oxidoreductase; Parents; Pathway interactions; Pharmaceutical Preparations; Phase; Plant Roots; Plasma; Pregnant Women; Property; Risk; Rodent; Route; Sampling; Scalp structure; Seborrheic dermatitis; Side; Signal Transduction; Skin; Skin Tissue; Stanolone; Steroid biosynthesis; Steroids; Symptoms; Testosterone; Therapeutic; Tissue Extracts; Tissues; Topical agent; Topical application; Toxic effect; Toxicity Tests; Toxicology; Woman; absorption; base; design; drug candidate; enantiomer; esterase; in vivo; inhibitor/antagonist; male; meetings; member; men; novel; prototype; public health relevance; receptor binding; sex; skin disorder; steroid hormone; steroid metabolism; uptake

DESCRIPTION: Androgen action is the net result of opposing pathways of steroid biosynthesis and metabolism. It is now widely recognized that testosterone (T) is an androgenic precursor of the more potent 5¿-dihydrotestosterone (DHT), produced by 5¿-reductase type 2. Circulating T and DHT also serve as precursors of estrogens through their conversion to estradiol and estrone by aromatase. Thus, regardless of gender, these secreted steroids are converted peripherally into divergent signals for two members of the steroid hormone nuclear receptor family. The overproduction of androgens in both sexes is the root cause of most acne (acne vulgaris), alopecia and seborrhea, and the practice of using antiandrogenic therapy in these disorders is accepted. However, the systemic antiandrogen side effects of marketed nonsteroidal androgen antagonists (flutamide, nilutamide, bicalutamide) and 5¿-reductase type 2 inhibitors (finasteride) are serious drawbacks to their repeated use, and some are contraindicated in pregnant women. While acne vulgaris is the most prevalent skin disorder in humans, the other diseases are also relatively common. All of the current therapies for these disorders, including over the counter medications, treat the symptoms but not the excess skin androgens. In addition, all current treatments for these disorders have local and systemic side effects. Severe forms of these skin disorders, e.g. cystic acne, are largely untreatable and represent a significant unmet medical need. We and our collaborators at Hygeia Therapeutics Inc. have identified a synthetic antiandrogenic compound - (S)-HYG-440 - a chiral ester that potently binds the androgen receptor and reduces androgenic functional activity in cell cultures. In contrast, its hydrolysis product - (S)-HYG-441 - is devoid of both activities. (S)-HYG-440, applied topically to one hamster flank, reduced the size of this organ but only on the ipsilateral side These results suggest that this drug is a "soft antiandrogen", expected to be active topically in androgen-dependent maladies of the skin and scalp, but to be hydrolyzed by plasma or tissue enzymes, thus terminating its systemic action. Indeed, (S)-HYG-440 is readily hydrolyzed after incubation in animal plasmas. The specific aims to answer the fundamental question "is (S)-HYG-440 actually a "soft" drug?" include: synthesis by yet newer methods of both (S)-HYG-440 and (S)-HYG-441 as candidate drug and metabolic product, respectively; the latter will serve also as toxicology sample and marker for further analyses; application of (S)-HYG-440 to the skin of hamsters, and analysis of plasma and tissue extracts for uptake and distribution of the parent compound and its conversion to (S)-HYG-441;and toxicity testing of the hydrolysis product (S)-HYG-441 in vitro and in vivo the hamster. Although inhibition of androgen action to treat acne, seborrhea and alopecia in men and women (and hirsutism in women) is efficacious, it can carry serious systemic risks. However, because all of these maladies are localized to the skin, it follows that local treatment would carry a higher benefit-to-risk ratio compared to orally administered therapies. Unlike all other antiandrogens or 5¿-reductase inhibitors on the market or in development, (S)-HYG-440 was designed to avoid systemic activity by taking advantage of esterases and hydrolases found in most tissues in the body for metabolic deactivation, i.e. as a metabolically "soft" drug. The antiandrogenic activity of the prototype compound (S)-HYG-440 may be limited to the parent drug because its putative hydrolysis product has no detectable affinity for the androgen receptor. An antiandrogen specifically designed to act locally would minimize or avoid unwanted systemic antiandrogen effects. The synthesis and discovery of an optimal locally active androgen antagonist to be applied to the skin to treat acne, alopecia, seborrhea (and hirsutism in women) are the subjects of this application.

描述：雄激素作用是相反的类固醇生物合成和代谢途径的结果。现在，人们广泛认识到，睾丸激素（T）是由5？还原酶2型产生的潜在5€ -Dihydrotostosterone（DHT）的雄激素前体的。循环T和DHT也通过对雌激酶的转化为雌激酶来充当雌激素的前体。无论性别如何，这些分泌的类固醇都被外围转化为两名类固醇马核受体家族成员的不同信号。两性中雄激素的过量生产是大多数痤疮（痤疮粉刺），脱发和皮脂腺的根本原因，并且接受了在这些疾病中使用抗二氧化碳疗法的实践。然而，销售的非甾体雄激素拮抗剂（氟丁二酰胺，尼罗二酰胺，双氨酰胺）和5雷克斯酶2型抑制剂（Finasteride）的全身性抗雄激素副作用是其重复使用的严重缺点，有些是禁忌的孕妇。虽然痤疮是痤疮是人类中最普遍的皮肤病，但其他疾病也相对普遍。这些疾病的所有当前疗法，包括在反药物上，都可以治疗症状，但不能治疗多余的皮肤雄激素。此外，所有目前对这些疾病的治疗方法都有局部和全身性副作用。这些皮肤疾病的严重形式，例如囊性痤疮在很大程度上是无法治疗的，代表了巨大的未满足的医疗需求。我们和我们在Hygeia Therapeutics Inc.的合作者已经确定了一种合成的抗雄激素化合物 - （S）-HYG -440-一种可能结合雄激素受体并降低细胞培养中雄激素功能活性的手性酯。相反，其水解产物 - （S）-HYG -441-没有两种活性。 （S）-HYG-440局部应用于一个仓鼠侧面，减小了该器官的大小，但仅在同侧这些结果这些结果表明，这种药物是一种“软抗抗原原”，预计将在皮肤和头皮的雄激素依赖性疾病中积极地积极，但可以通过血浆或组织或组织的enzemessectiens进行系统，从而使其具有系统的作用。确实，在动物等离子体中孵育后，（S）-HYG-440很容易水解。具体目的是回答基本问题“是（S）-HYG-440实际上是“软”药物？包括：通过（S）-HYG-440和（S）-HYG-441作为候选药物和代谢产物的较新方法的合成；后者还将作为毒理学样本和标记以进行进一步分析。 （S）-HYG-440应用于仓鼠的皮肤，以及分析血浆和组织提取物，以摄取和分布父型化合物及其转化为（S）-HYG-441；水解产物的毒性测试（S）-HYG-441在体外和体内仓鼠。尽管抑制雄激素作用以治疗痤疮，男性和女性（女性的毛发和脱发）有效，但它可以带来严重的系统性风险。但是，由于所有这些疾病都位于皮肤上，因此与口服治疗相比，局部治疗将具有更高的利益风险比率。与市场或发育中的所有其他抗二元蛋白或5¿-还原酶抑制剂不同，（S）-HYG-440旨在通过利用体内的大多数组织中发现的酯酶和水解酶进行代谢失活，即作为代谢性“软”药物，旨在避免全身活动。原型化合物（S）-HYG-440的抗雄激素活性可能仅限于母体药物，因为其推定的水解产物对雄激素受体没有可检测的亲和力。专门设计用于本地作用的抗雄激素可以最大程度地减少或避免不必要的全身抗二氧化碳作用。该应用的主题是该应用的主题。