Small Molecule Target for Inhibition of Cortisol in Cushing's Syndrome

抑制库欣综合征皮质醇的小分子靶点

• 批准号: 8834802
• 负责人: PAUL D CROWE
• 金额: $ 22.32万
• 依托单位: ORPHAGEN PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834802
• 关键词: Adrenal Gland Hyperfunction; Adrenal Gland Neoplasms; Adrenal Glands; Adrenocortical carcinoma; Adverse effects; Affect; Androgens; Assessment of Gonadal Function; Biochemical; Biological Assay; Biological Availability; Brain; CYP11B2 gene; CYP21A2 gene; Cancer cell line; Cardiovascular system; Cell Culture Techniques; Cell Membrane Permeability; Cells; Chemistry; Cholesterol; Chronic; Clinical; Corticosterone; Corticotropin; Cortodoxone; Cushing Syndrome; Cytochrome P450; Deoxycorticosterone; Development; Diabetes Mellitus; Diagnosis; Dose; Dose-Limiting; Drug Interactions; Drug Kinetics; Drug Targeting; Endocrine system; Endometrial; Ensure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Excision; Exposure to; Family; Female; Foundations; Functional disorder; Gene Expression; Generations; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Glucose Intolerance; Goals; Growth; Half-Life; Hemorrhage; Hepatotoxicity; Human; Hydrocortisone; Hydroxyprogesterone; Hyperglycemia; Hypertension; In Vitro; Inhibitory Concentration 50; Ketoconazole; Label; Liver Microsomes; Malignant neoplasm of adrenal cortex; Measures; Mediating; Medical; Metabolic; Metyrapone; Mifepristone; Mineralocorticoids; Modeling; Monkeys; Mood Disorders; Morbidity - disease rate; Mus; Nuclear Orphan Receptor; Nuclear Receptors; Obesity; One-Step dentin bonding system; Operative Surgical Procedures; Oral; Orphan; Osteoporosis; Output; Patients; Penetration; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Pituitary Gland; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Plasma; Pregnenolone; Production; Progesterone Receptors; Property; Publishing; Pump; Rattus; Recurrence; Risk; SF1; Safety; Signs and Symptoms; Solubility; Specificity; Steroid 11-beta-Monooxygenase; Steroid biosynthesis; Steroids; Symptoms; Testing; Testosterone; Toxic effect; Toxicology; United States; Virilism; Weight Gain; Woman; analog; aqueous; base; design; drug discovery; improved; in vivo; inhibitor/antagonist; lipophilicity; mortality; mouse model; novel; novel therapeutic intervention; osmotic minipump; outcome forecast; public health relevance; receptor; scaffold; small molecule; somatostatin analog; steroid hormone; transcription factor; tumor

 DESCRIPTION (provided by applicant): Endogenous Cushing's syndrome is a classic dysfunction of the endocrine system caused by prolonged exposure to inappropriately high levels of cortisol. The condition is tumor-driven and leads to obesity, diabetes, hypertension and psychiatric dysfunction, symptoms which improve with a reduction in cortisol. Cushing's syndrome disproportionately affects females, who make up 75% of the 3,000 new cases diagnosed each year in the United States. Two drugs recently approved for Cushing's, mifepristone and pasireotide, underscore the importance of developing new therapies. Pasireotide, indicated for patients with an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor (Cushing's Disease), is effective in just 25% of cases and can cause hyperglycemia and diabetes. Mifepristone blocks glucocorticoid and progesterone receptors, leading to elevated cortisol and endometrial bleeding in women. Significantly, medical therapy of hypercortisolism in Cushing's is still predominantly based on off-label use of steroidogenic enzyme inhibitors that reduce cortisol, but have dose-limiting side effects such as hepatotoxicity (ketoconazole) and accumulation of steroid precursors upstream of cortisol leading to virilization in women or, less commonly, hypertension (metyrapone). Orphagen has identified the first potent small molecule antagonists to steroidogenic factor-1 (SF-1), an orphan receptor and transcription factor that regulates adrenal steroid hormone output. SF-1 antagonists block glucocorticoid production in primary rat and human adrenal cell cultures by >80% and similarly suppress pregnenolone, the first major biosynthetic steroid and the precursor to all other adrenal steroids. The antagonists are specific to SF-1 and therefore should avoid the peripheral toxicity associated with non-specific cytochrome P450 enzyme inhibitors like ketoconazole. Moreover, the SF-1 antagonist drug class, by inhibiting more than one step of adrenal steroid synthesis, should limit or avoid side effects seen with metyrapone. The objective of this proposal is to identify a first-in-class, potent and efficacious SF-1 antagonist that suppresses glucocorticoid synthesis in vivo. In Aim 1, we will design and synthesize analogs of OR-907, a first generation SF-1 antagonist, with the goal of identifying compounds with improved aqueous solubility and in vitro metabolic stability in liver microsomes (t1/2 >3h) while preserving potency (SF-1 IC50 <50nM). In Aim 2, we will evaluate pharmacokinetic properties in mice to ensure adequate oral bioavailability (>30%) and plasma (t1/2 >2h) necessary for in vivo efficacy studies. In Aim 3 we test SF-1 antagonists in mice exposed to ACTH via an osmotic pump to model chronic stimulation of adrenal function. In addition, we conduct a preliminary assessment of gonadal function in SF-1 antagonist-treated mice. The proposed Aims create a foundation for further drug discovery efforts to identify a first-in-class SF-1 antagonist clinical candidate. In he longer-term, our goal is to develop a superior medical therapy for Cushing's syndrome based on a novel mechanism of action mediated by the SF-1 receptor.

 描述（由申请人提供）：内源性库欣综合征是一种典型的内分泌系统功能障碍，由长期暴露于不适当的高水平皮质醇引起。这种情况是由肿瘤引起的，会导致肥胖、糖尿病、高血压和精神功能障碍，这些症状会随着皮质醇的减少而改善。库欣综合征对女性的影响不成比例，在美国每年诊断的3,000例新病例中，女性占75%。最近批准的两种治疗库欣氏症的药物，米非司酮和帕瑞肽，强调了开发新疗法的重要性。帕瑞肽适用于促肾上腺皮质激素（ACTH）分泌型垂体瘤（库欣病）患者，仅对25%的病例有效，可引起高血糖和糖尿病。米非司酮阻断糖皮质激素和孕激素受体，导致皮质醇升高和子宫内膜出血。值得注意的是，库欣氏皮质醇增多症的药物治疗仍然主要基于类固醇生成酶抑制剂的标签外使用，这些抑制剂可降低皮质醇，但具有剂量限制性副作用，如肝毒性（酮康唑）和皮质醇上游类固醇前体蓄积，导致女性男性化，或较不常见的高血压（甲吡酮）。Orphagen已经确定了类固醇生成因子-1（SF-1）的第一个有效的小分子拮抗剂，SF-1是一种孤儿受体和转录因子，可调节肾上腺类固醇激素的分泌。SF-1拮抗剂阻断原代大鼠和人肾上腺细胞培养物中糖皮质激素的产生达>80%，并且类似地抑制阿替烯醇酮，阿替烯醇酮是第一种主要的生物合成类固醇和所有其他肾上腺类固醇的前体。拮抗剂对SF-1具有特异性，因此应避免与非特异性细胞色素P450酶抑制剂（如酮康唑）相关的外周毒性。此外，SF-1拮抗剂类药物通过抑制肾上腺类固醇合成的一个以上步骤，应限制或避免甲吡酮的副作用。该建议的目的是确定一种一流的，强效和有效的SF-1拮抗剂，抑制体内糖皮质激素的合成。在目标1中，我们将设计和合成第一代SF-1拮抗剂OR-907的类似物，目的是鉴定具有改善的水溶性和在肝微粒体中的体外代谢稳定性（t1/2 > 3 h）同时保持效力的化合物 (SF-1 IC50 <50 nM）。在目标2中，我们将评估小鼠的药代动力学特性，以确保体内功效研究所需的足够的口服生物利用度（>30%）和血浆（t1/2 > 2 h）。在目标3中，我们测试SF-1拮抗剂在小鼠中暴露于ACTH通过渗透泵模型慢性刺激肾上腺功能。此外，我们对SF-1拮抗剂处理的小鼠的性腺功能进行了初步评估。提出的目标为进一步的药物发现工作奠定了基础，以确定一流的SF-1拮抗剂临床候选药物。从长远来看，我们的目标是根据SF-1受体介导的新的作用机制，开发出一种上级药物治疗库欣综合征。