Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study复制标题

Osilodrostat是一种潜在的新型类固醇生成抑制剂，用于治疗库欣综合征: 一项体外研究

Cushing syndrome (CS) is characterized by chronic exposure to excess glucocorticoids, resulting in substantial multisystem morbidity and, when untreated, increased mortality. ACTH-dependent CS can be caused by a corticotroph pituitary adenoma [Cushing disease (CD)] or, more rarely, by ectopic ACTH secretion by a neuroendocrine tumor (ectopic ACTH syndrome). ACTH-independent CS is in most cases caused by a unilateral cortisol-producing adrenocortical adenoma (ACA) and less frequently by an adrenocortical carcinoma (ACC) or bilateral adrenal hyperplasia. The first-line treatment modality in all types of CS is surgery. There are several conditions, however, such as surgical failure, metastatic or occult disease, or high surgical risk, in which other treatment modalities such as medical therapy are indicated. Traditionally, medical treatment options for CS can be divided into three categories: (i) pituitary-targeting drugs (i.e., pasireotide and cabergoline); (ii) glucocorticoid receptor blockers (e.g., mifepristone); and (iii) adrenocortical steroidogenesis inhibitors that directly suppress cortisol production via inhibition of steroidogenic enzymes. Two of the most frequently used steroidogenesis inhibitors are metyrapone and ketoconazole. Although it is known that metyrapone selectively inhibits the last step in the cortisol biosynthesis via inhibition of CYP11B1 (11b-hydroxylase), it also inhibits CYP11B2 (aldosterone synthase). More recently, in vitro data obtained in a rodent model even suggested that metyrapone has greater potency to inhibit CYP11B2, a feature not previously recognized. Ketoconazole, originally developed as an antifungal agent, is known to inhibit several steps in adrenal steroid synthesis. Although several medical therapies are currently available, not all patients respond and many patients experience side effects. Metyrapone can cause hypertension, edema, hypokalemia, acne, and hirsutism resulting from an increase of mineralocorticoid precursors and adrenal androgens. The most important adverse events of ketoconazole include hepatotoxicity and gastrointestinal symptoms.

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