Steroid 11β-hydroxylase inhibitor for Cushing's Syndrome

类固醇 11β-羟化酶抑制剂治疗库欣综合征

• 批准号: 9465756
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 22.27万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9465756
• 关键词: Adrenal Gland Neoplasms; Adrenal Glands; Aldosterone; Aldosterone Antagonists; Animal Model; Applications Grants; Autoimmune Process; Blood Pressure; CYP11B1 gene; CYP11B2 gene; CYP17A1 gene; CYP19A1 gene; CYP3A4 gene; Cardiovascular Diseases; Central obesity; Clinical; Clinical Trials; Corticosterone; Corticotropin; Crystallization; Cushing Syndrome; Cytochrome P450; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Effectiveness; Electrolytes; Enzyme Inhibitor Drugs; Enzymes; Face; Future; Glucocorticoids; Goals; Homology Modeling; Hydrocortisone; Hypernatremia; Hypertension; Hypokalemia; Inflammatory; Lead; Measurement; Metyrapone; Mixed Function Oxygenases; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Oral; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pituitary Gland Adenoma; Pre-Clinical Model; Production; Property; Pump; Radiation; Risk; Safety; Series; Serum; Solid; Steroids; Structure; Testing; Toxicology; Weight Gain; associated symptom; design; drug efficacy; efficacy evaluation; efficacy study; efficacy testing; in vivo; inhibitor/antagonist; mouse model; neoplastic; programs; small molecule inhibitor; therapeutic evaluation; urinary

Cushing’s Syndrome (CS) is caused by sustained elevated levels of cortisol. Patients with CS often have high blood pressure, abdominal obesity, a round red face, and are at an increased risk of morbidity, especially related to cardiovascular disease. CS can result from glucocorticoid medications that are used to treat inflammatory, autoimmune and neoplastic disorders. Other causes for CS are pituitary adenomas and adrenal tumors that lead to excessive cortisol production by the adrenal glands. Treatment depends on the cause of CS, but often involves pharmacological inhibition of cortisol production. Steroid 11β-hydroxylase, encoded by the CYP11B1 gene, is the enzyme responsible for the last steps of cortisol production. Several medications are known to inhibit steroid 11β-hydroxylase, but they also inhibit other cytochrome P450 enzymes, thus limiting their effectiveness and use for CS patients. Recent clinical trials with the potent steroid 11β-hydroxylase inhibitor Osilodrostat (LCI699) have shown promise, but LCI699 has poor selectivity and is in fact a more potent inhibitor of aldosterone production than of cortisol production. As part of its successful medicinal chemistry program to identify potent and selective inhibitors of Aldosterone Synthase (AS, encoded by CYP11B2), Angion has also identified compounds which potently inhibit the closely related CYP11B1. The present grant proposal aims for Angion to optimize this series of compounds for potency and selectivity towards CYP11B1 and thus identify truly selective steroid 11β-hydroxylase inhibitors for use in CS patients.

库欣综合征（CS）是由皮质醇水平持续升高引起的。CS患者通常具有高 高血压，腹部肥胖，圆脸，并在发病的风险增加，特别是 与心血管疾病有关。CS可由糖皮质激素药物引起， 炎性、自身免疫性和肿瘤性疾病。其他原因为CS是垂体腺瘤和肾上腺 导致肾上腺分泌过多皮质醇的肿瘤。治疗取决于病因 CS，但通常涉及皮质醇产生的药理学抑制。类固醇11β-羟化酶，由 CYP 11B 1基因是负责皮质醇产生的最后步骤的酶。有几种药物是 已知抑制类固醇11β-羟化酶，但它们也抑制其他细胞色素P450酶，因此限制了 其有效性和用于CS患者。强效类固醇11β-羟化酶的最新临床试验 抑制剂Osilodrostat（LCI 699）已显示出前景，但LCI 699选择性差，实际上是一种更 强有力的抑制剂醛固酮生产比皮质醇生产。作为其成功的医学的一部分， 化学程序，以确定有效的和选择性的抑制剂醛固酮合成酶（AS，编码 CYP 11B 2），Angion还鉴定了有效抑制密切相关的CYP 11B 1的化合物。的 目前的拨款计划旨在Angion优化这一系列化合物的效力和选择性 CYP 11B 1，从而确定用于CS患者的真正选择性类固醇11β-羟化酶抑制剂。