STEROID ANATAGONISTS

类固醇拮抗剂

• 批准号: 3919247
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3919247
• 关键词: Cushing's syndrome; child (0-11); corticosteroid analog; drug design /synthesis /production; drug metabolism; endocrine pharmacology; glucocorticoids; hormone inhibitor; human subject; human therapy evaluation; hyperadrenalism; pituitary adrenal axis; progestins

Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered only recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. Initially, we proved that glucocorticoid antagonists can be developed by modifications of the 11-position of the steroidal C ring of glucocorticoids. Then we tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis, when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. We have treated 8 patients and are currently enlarging the therapy series. Given to women in single monthly doses during the luteal phase of the cycle RU 486 causes vaginal bleeding. The subsequent cycle is of normal duration. This suggests that single doses of RU 486 could be used for contraception.

存在临床上有用的雌激素、雄激素和 盐皮质激素。 糖皮质激素或糖皮质激素的拮抗剂 已发现具有潜在临床用途的孕激素 就在最近。 该项目的目标是开发和 研究分子作用机制和人类应用 这两类类固醇的拮抗剂。 最初，我们证明糖皮质激素拮抗剂可以 通过修饰甾体 C 的 11 位而开发 糖皮质激素环。 然后我们测试了原型 最近开发的糖皮质激素-孕激素拮抗剂（RU 486） 鲁塞尔-加州大学洛杉矶分校。 这种化合物对人类有很强的亲和力 糖皮质激素和孕激素受体，不含激动剂 对小实验动物的影响。 给予非人类灵长类动物或人类 RU 486 会导致长期 血浆 ACTH、皮质醇和精氨酸加压素升高，所有 先前服用糖皮质激素可预防的变化 （地塞米松）。 这表明抗糖皮质激素可能 用于挑战下丘脑-垂体-肾上腺轴，当 患有这种疾病的患者需要进行临床测试 轴。重症库欣病患者的抗糖皮质激素治疗 由于异位 ACTH 分泌或肾上腺皮质肿瘤引起的综合征 导致临床表现缓解 皮质醇增多症。 我们已经治疗了8名患者，目前正在治疗中 扩大治疗系列。 在黄体期给予女性每月一次剂量 RU 486 周期会导致阴道流血。 接下来的循环是 正常持续时间。 这表明单剂量的 RU 486 可以用于避孕。