A Soft Topical Antiandrogenic Drug

描述：雄激素作用是类固醇生物合成和代谢的相反途径的最终结果。现在人们普遍认为，睾酮(T)是更有效的5 -二氢睾酮（DHT）的雄激素前体，由5 -还原酶2型产生。循环T和DHT也作为雌激素的前体，通过芳香化酶转化为雌二醇和雌酮。因此，无论性别如何，这些分泌的类固醇都被外周转化为类固醇激素核受体家族的两个成员的不同信号。男性和女性雄激素分泌过多是大多数痤疮（寻常痤疮）、脱发和脂溢症的根本原因，在这些疾病中使用抗雄激素治疗的做法是被接受的。然而，已上市的非甾体雄激素拮抗剂（氟他胺、尼鲁胺、比卡鲁胺）和5¿-还原酶2型抑制剂（非那雄胺）的系统性抗雄激素副作用是反复使用的严重缺陷，有些是孕妇的禁忌症。寻常痤疮是人类最常见的皮肤病，其他疾病也相对常见。目前针对这些疾病的所有治疗方法，包括非处方药物，治疗的是症状，而不是皮肤上多余的雄激素。此外，目前对这些疾病的所有治疗都有局部和全身副作用。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，代表着未得到满足的重大医疗需求。我们和Hygeia Therapeutics公司的合作者已经鉴定出一种合成的抗雄激素化合物- (S)- hyg -440 -一种在细胞培养中有效结合雄激素受体并降低雄激素功能活性的手性酯。相反，其水解产物- (S)- hyg -441 -不具有这两种活性。(S)-HYG-440局部应用于一只鼠的侧腹，减少了该器官的大小，但仅在同侧。这些结果表明，该药物是一种“软抗雄激素”，预计在皮肤和头皮的雄激素依赖性疾病中局部有效，但会被血浆或组织酶水解，从而终止其全身作用。事实上，(S)-HYG-440在动物血浆中孵育后很容易水解。回答“(S)-HYG-440实际上是一种“软”药物吗？”这一基本问题的具体目标包括：用更新的方法分别合成(S)-HYG-440和(S)-HYG-441作为候选药物和代谢产物；后者也将作为毒理学样本和进一步分析的标记物；(S)-HYG-440在仓鼠皮肤上的应用，分析血浆和组织提取物对母体化合物的吸收和分布及其向(S)-HYG-441的转化；水解产物(S)-HYG-441对仓鼠体外和体内的毒性试验。虽然抑制雄激素的作用对治疗男性和女性的痤疮、脂溢症和脱发（以及女性的多毛症）是有效的，但它可能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，因此与口服治疗相比，局部治疗将具有更高的收益-风险比。与市场上或正在开发的所有其他抗雄激素或5¿-还原酶抑制剂不同，(S)-HYG-440通过利用体内大多数组织中发现的酯酶和水解酶来代谢失活，从而避免全身活性，即作为一种代谢“软”药物。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到的亲和力。专门设计用于局部作用的抗雄激素将尽量减少或避免不必要的全身抗雄激素作用。合成和发现一种最佳的局部活性雄激素拮抗剂，应用于皮肤治疗痤疮，脱发，脂溢症（和女性多毛症）是本应用的主题。

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.