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.

项目摘要库欣综合征的临床体征包括脂肪垫的生长（锁骨，颈部，脸部，后备箱），过多的出汗，毛细血管扩张，皮肤稀疏，肌肉无力，多毛，抑郁/焦虑，高血压，骨质疏松症，胰岛素抵抗，高血糖，心脏病和范围其他代谢障碍导致发病率高。如果以其严重的形式受到不足的控制，库欣综合症与高死亡率有关。库欣综合症最常见的形式是由于分泌过量的ACTH的垂体皮质营养细胞的微神经瘤引起的库欣病。库欣氏病的一线治疗是切除垂体肿瘤的类手术。医疗的当手术延迟，禁忌或失败时，需要治疗。肾上腺酶抑制剂（Metyrapone，酮康唑）防止皮质醇的合成，并可以快速改善症状。然而，元元酮与女性的毛发病有关（由于雄激素类固醇的积累）和必须仔细监测患者，以避免肾上腺低下。酮康唑通常需要逐渐需要增加剂量以维持疾病控制，但最终受到该药物的肝毒性的限制。在此外，它是CYP3A4的有效抑制剂，导致多种药物相互作用。最近批准的生长抑素激动剂，pasireotide抑制了ACTH的分泌，但在III期试验中只有15-26％实现了无尿无尿皮质醇的归一化，而有73％的患者经历了高血糖相关的患者由于化合物对胰岛素分泌的有效抑制作用而导致的不良事件。因此明显的未得到医疗需要改善药物治疗库欣氏病。在这里，我们建议开发一种新型的小分子口服药物，以防止ACTH过度肾上腺刺激。这些药物应将皮质醇水平归一化，而不会与目前可用的肾上腺酶抑制剂产生过量产生肾上腺雄激素或肝毒性。重点化学文库的设计和筛选导致较高的命中率（60％）以及一个类似药物的药物化学起点家族的新兴结构活动关系。在这里，我们建议使用药物化学探索这个化学系列并建立必要的反屏幕，以证明这种方法的可行性。如果成功，在第二阶段的药物化学工作扩大将导致新的候选药物为了治疗库欣氏病，准备开始开始临床试验所需的临床前活动。

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：
10.1021/acsmedchemlett.3c00514
发表时间：
2024
期刊：
ACS medicinal chemistry letters
影响因子：
4.2
作者：
Kim,SunHee;Han,Sangdon;Zhao,Jian;Wang,Shimiao;Kusnetzow,AnaKarin;Reinhart,Greg;Fowler,MelissaA;Markison,Stacy;Johns,Michael;Luo,Rosa;Struthers,RScott;Zhu,Yunfei;Betz,StephenF
通讯作者：
Betz,StephenF