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

基本信息

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
项目类别：
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

项目摘要

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。库欣综合征患者的皮质醇水平通常较高。血液，腹部肥胖，圆红脸压力，发病风险增加，尤其是与心血管疾病相关的 CS 可能由用于治疗的糖皮质激素药物引起。 CS 的其他原因包括垂体腺瘤和肾上腺肿瘤。导致肾上腺产生过多皮质醇的肿瘤治疗取决于其病因。 CS，但通常涉及皮质醇产生的药理抑制，由类固醇 11β-羟化酶编码。 CYP11B1 基因是负责皮质醇产生最后步骤的酶。已知可抑制类固醇 11β-羟化酶，但它们也会抑制其他细胞色素 P450 酶，从而限制最近对强效类固醇 11β-羟化酶进行的临床试验。抑制剂奥西洛司他 (LCI699) 已显示出前景，但 LCI699 的选择性较差，实际上是一种更醛固酮生成的有效抑制剂比皮质醇生成的抑制剂更有效，这是其成功药用的一部分。化学程序来鉴定醛固酮合酶（AS，编码为 CYP11B2），Angion 还鉴定出可有效抑制密切相关的 CYP11B1 的化合物。目前的资助提案旨在 Angion 优化这一系列化合物的效力和选择性 CYP11B1，从而确定真正选择性的类固醇 11β-羟化酶抑制剂，用于 CS 患者。