Steroid 11β-hydroxylase inhibitor for Cushing's Syndrome

库欣综合征(CS)是由持续升高的皮质醇水平引起的。CS患者常有高 血压、腹型肥胖、红脸圆润，患病风险增加，尤其是 与心血管疾病有关。CS可由用于治疗的糖皮质激素药物引起 炎症性、自身免疫性和肿瘤性疾病。导致CS的其他原因是垂体腺瘤和肾上腺 导致肾上腺产生过多皮质醇的肿瘤。治疗取决于疾病的原因。 CS，但通常涉及药物抑制皮质醇的产生。类固醇11β-羟基酶，由 细胞色素P11B1基因是负责皮质醇产生的最后几步的酶。有几种药物是 已知可以抑制类固醇11β-羟基酶，但它们也抑制其他细胞色素P450酶，从而限制 它们对CS患者的有效性和使用。强效类固醇11β羟基酶的最新临床试验 抑制剂Osilodrostat(LCI699)已显示出良好的前景，但LCI699选择性较差，实际上是一种更 对醛固酮产生的抑制作用强于对皮质醇产生的抑制作用。作为其成功的药物的一部分 用于鉴定有效和选择性的醛固酮合酶(AS)抑制剂的化学程序，编码方式为 除了CYP11B2)，Angion还发现了能有效抑制密切相关的CYP11B1的化合物。这个 目前的赠款提案旨在为Angion优化这一系列化合物的效力和选择性 从而确定用于CS患者的真正选择性的类固醇11β-羟基酶抑制剂。

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.