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：雄激素作用是类固醇生物合成和代谢途径竞争的最终结果，现在人们广泛认识到睾酮 (T) 是更有效的 5¿ 的雄激素前体。 -二氢睾酮 (DHT)，由 5¿ -还原酶 2 型。循环中的 T 和 DHT 也可通过芳香酶转化为雌二醇和雌酮，从而充当雌激素的前体。因此，无论性别如何，这些分泌的类固醇都会在外周转化为类固醇激素核受体家族两个成员的不同信号。两性雄激素的过量产生是大多数痤疮（寻常痤疮）、脱发和皮脂溢的根本原因，而使用抗雄激素治疗的实践然而，这些疾病已被接受，但市售非甾体雄激素拮抗剂（氟他胺、尼鲁米特、比卡鲁胺）和 5¿ 2 型还原酶抑制剂（非那雄胺）的严重缺点是其重复使用，并且有些是孕妇禁忌的。虽然寻常痤疮是人类最常见的皮肤病，但其他疾病也相对常见。这些疾病，包括非处方药，只能治疗症状，但不能治疗皮肤雄激素过多。此外，目前治疗这些疾病的方法都具有严重的局部和全身副作用，例如囊肿性痤疮。我们和 Hygeia Therapeutics Inc. 的合作者发现了一种合成的抗雄激素化合物 - (S)-HYG-440 - 一种手性酯，可有效结合雄激素受体并降低雄激素功能活性。相反，其水解产物 - (S)-HYG-441 - 缺乏这两种活性，局部应用于。一个仓鼠胁腹，缩小了该器官的大小，但仅限于同侧。这些结果表明，该药物是一种“软性抗雄激素”，预计在局部治疗雄激素依赖性皮肤和头皮疾病时具有活性，但会被水解事实上，(S)-HYG-440 在动物血浆中孵育后很容易水解，其具体目的是回答“是”这一基本问题。 (S)-HYG-440 实际上是一种“软”药物？”包括：通过更新的方法合成 (S)-HYG-440 和 (S)-HYG-441 分别作为候选药物和代谢产物；后者还将作为毒理学样品和标记物，用于将 (S)-HYG-440 应用于仓鼠皮肤，并分析血浆和组织提取物的母体化合物的吸收和分布及其转化为(S)-HYG-441；以及水解产物(S)-HYG-441在仓鼠体外和体内的毒性测试，尽管抑制雄激素作用，治疗男性和女性的痤疮、皮脂溢和脱发（以及多毛症）。女性）虽然有效，但可能会带来严重的系统性风险。然而，由于所有这些疾病都局限于皮肤，因此与局部治疗相比，局部治疗的获益风险比更高。与所有其他抗雄激素或 5¿作为市场上或正在开发的还原酶抑制剂，(S)-HYG-440 旨在通过利用体内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“软”药物来避免全身活动。原型化合物 (S)-HYG-440 的抗雄激素活性可能仅限于母体药物，因为其假定的水解产物对雄激素受体没有可检测的亲和力。专门设计用于局部作用的抗雄激素可以最大限度地减少或避免不必要的全身性抗雄激素作用。本研究的主题是合成和发现一种最佳的局部活性雄激素拮抗剂，用于皮肤治疗痤疮、脱发、皮脂溢（和女性多毛症）。应用。