Discovery of novel small molecule drugs for Cushing's disease

发现治疗库欣病的新型小分子药物

基本信息

批准号：
9407461
负责人：
RICHARD SCOTT STRUTHERS
金额：
$ 29.95万
依托单位：
CRINETICS PHARMACEUTICALS, INC.
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：
2017-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407461
关键词：
Adrenal Glands Adrenal gland hypofunction Adverse effects Adverse event Agonist Anabolism Androgens Anxiety Back Binding Bioavailable Biological Assay Biological Availability Blood Circulation Blood capillaries CYP3A4 gene Cell surface Cells Characteristics Chemicals Clinical Clinical Trials Complex Congenital adrenal hyperplasia Corticotropin Corticotropin Receptors Cushing Syndrome Cyclic AMP Cytochrome P450 Disease Drug Interactions Drug Targeting Endocrine System Diseases Endocrinology Enzyme Inhibitor Drugs Evaluation Face Family Fatty acid glycerol esters Future Glucocorticoids Goals Government Growth Heart Diseases Hepatotoxicity Hirsutism Human Hydrocortisone Hyperglycemia Hypertension Insulin Resistance Intervention Ion Channel Ketoconazole Lead Legal patent Libraries Literature Liver Measures Medical Mental Depression Metabolic Metyrapone Monitor Morbidity - disease rate Muscle Weakness Neck Operative Surgical Procedures Oral Osteoporosis Patients Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Pituitary Corticotropin Secreting Adenoma Pituitary Gland Pituitary Gland Adenoma Pituitary Neoplasms Pituitary-dependent Cushing&apos s disease Production Property Proteins Rattus Reporting Safety Series Skin Solubility Somatostatin Steroids Structure Structure-Activity Relationship Sweat Sweating Testing Therapeutic Thinness Toxicology Woman androgenic base capillary chemical stability design disorder control dosage drug candidate drug discovery experience improved in vitro Assay inhibitor/antagonist innovation insulin secretion melanocortin receptor member mortality novel novel therapeutics phase III trial pre-clinical prevent receptor research clinical testing screening small molecule small molecule libraries symptomatic improvement trafficking urinary

项目摘要

Project Summary Clinical signs of Cushing's syndrome include growth of fat pads (collarbone, back of neck, face, trunk), excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease and a range of other metabolic disturbances resulting in high morbidity. If inadequately controlled in its severe forms, Cushing's syndrome is associated with high mortality. The most common form of Cushing's syndrome is Cushing's disease due to microadenomas of pituitary corticotrophic cells that secrete excess ACTH. First-line therapy for Cushing's disease is transphenoidal surgery to remove the pituitary tumor. Medical therapy is required when surgery is delayed, contraindicated or unsuccessful. Adrenal enzyme inhibitors (metyrapone, ketoconazole) prevent the synthesis of cortisol and can rapidly improve symptoms. However, metyropone is associated with hirsuitism in women (because of the accumulation of androgenic steroids) and patients must be monitored carefully to avoid hypoadrenalism. Ketoconazole often requires progressively increasing dosage to maintain disease control but this is ultimately limited by the hepatotoxicity of the drug. In addition, it is a potent inhibitor of CYP3A4 resulting in multiple drug-interactions. The recently approved somatostatin agonist, pasireotide inhibits ACTH secretion but only 15-26% of patients in a Phase III trial achieved normalization of urinary free cortisol while 73% of patients experienced a hyperglycemia-related adverse event due to the compound's potent inhibition of insulin secretion. Therefore a significant unmet medical need exists for improved agents to treat Cushing's disease. Here we propose to develop a novel class of small molecule, oral drugs to prevent excessive adrenal stimulation by ACTH. These agents should normalize cortisol levels, without the excess production of adrenal androgens or hepatotoxicity found with currently available adrenal enzyme inhibitors. Design and screening of a focused chemical library resulted in a high hit rate (60%) and emerging structure activity relationships of a family of drug-like starting points for medicinal chemistry. Here we propose to use medicinal chemistry to explore this chemical series and establish necessary counter-screens in order to demonstrate feasibility of this approach. If successful, an expanded medicinal chemistry effort in Phase II will result in a novel drug candidate for the treatment of Cushing's disease ready for preclinical activities needed to begin clinical trials.

项目概要库欣综合征的临床症状包括脂肪垫生长（锁骨、颈后、面部、躯干）、出汗过多，毛细血管扩张，皮肤变薄，肌肉无力，多毛症，抑郁/焦虑、高血压、骨质疏松、胰岛素抵抗、高血糖、心脏病等其他代谢紊乱导致高发病率。如果其严重形式控制不充分，库欣综合征与高死亡率相关。库欣综合征最常见的形式是库欣病是由分泌过量 ACTH 的垂体促肾上腺皮质细胞微腺瘤引起的。库欣病的一线治疗是经蝶手术切除垂体瘤。医疗的当手术延迟、存在禁忌或不成功时，需要进行治疗。肾上腺酶抑制剂（甲吡酮、酮康唑）阻止皮质醇的合成，可以迅速改善症状。然而，甲吡酮与女性多毛症有关（由于雄激素类固醇的积累）必须仔细监测患者以避免肾上腺功能减退。酮康唑通常需要逐渐增加剂量以维持疾病控制，但这最终受到药物肝毒性的限制。在此外，它是 CYP3A4 的有效抑制剂，可导致多种药物相互作用。最近批准的生长抑素激动剂帕瑞肽可抑制 ACTH 分泌，但在 III 期试验中仅抑制 15-26% 的患者尿游离皮质醇实现正常化，同时 73% 的患者出现与高血糖相关的症状由于该化合物有效抑制胰岛素分泌而引起的不良事件。因此，一个重大的未满足医学上需要改进治疗库欣病的药物。在这里，我们建议开发一类新型小分子口服药物，以防止 ACTH 过度刺激肾上腺。这些药物应该使皮质醇水平正常化，而不会产生过量的肾上腺雄激素或目前可用的肾上腺酶抑制剂所发现的肝毒性。重点化学库的设计和筛选带来了高命中率 (60%) 和一系列药物化学起始点的新兴结构活性关系。在这里，我们建议使用药物化学来探索该化学系列并建立必要的反筛选，以证明该方法的可行性。如果成功，第二阶段的扩大药物化学工作将产生一种新的候选药物为治疗库欣病做好开始临床试验所需的临床前活动的准备。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（2）

Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist.

CRN04894 的发现：一种新型强效选择性 MC2R 拮抗剂。

DOI：
发表时间：
2024-04-11
期刊：
影响因子：
4.2
作者：
Kim, Sun Hee;Han, Sangdon;Zhao, Jian;Wang, Shimiao;Kusnetzow, Ana Karin;Reinhart, Greg;Fowler, Melissa A;Markison, Stacy;Johns, Michael;Luo, Rosa;Struthers, R Scott;Zhu, Yunfei;Betz, Stephen F
通讯作者：
Betz, Stephen F