Identification of Novel ACTH Small Molecule Antagonists

新型 ACTH 小分子拮抗剂的鉴定

• 批准号: 7156128
• 负责人: ILYA OKUN
• 金额: $ 37.67万
• 依托单位: CHEMDIV, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156128
• 关键词: adrenal disorder; adrenocorticotropic hormone; arrestins; biotechnology; computer assisted sequence analysis; computer simulation; computer system design /evaluation; cyclic AMP; drug discovery /isolation; green fluorescent proteins; hormone inhibitor; hormone receptor; microarray technology; molecular biology information system; molecular cloning; peptide library; receptor binding; small molecule; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): Development of drugs based on the MC2R antagonists will directly benefit children with CAH and Cushing's diseases, and will help us to understand MC2R's role in metabolic pathways. The long term goal of this project is to discover small molecule inhibitors of MC2 receptor and develop drugs to treat several metabolic diseases including CAH and Cushing's diseases afflicting children. Our Phase I studies to identify novel ACTH small molecule antagonists were successful; we were able to identify 3 novel non-peptide small molecule ACTH antagonists that have high affinity to the MC2R. The inhibitors belong to the same chemotype with a similar chemical backbone. These compounds are full ACTH antagonists that potently inhibit ACTH-stimulated adrenal cell activity. We have achieved the Phase I goals and discovered a novel series of small molecule non-peptide ACTH antagonists. Phase II of this project will be dedicated to extending our studies of ACTH antagonists by examining structure-activity relationships using series analogs of identified inhibitors to assess their ACTH antagonist potency, specificity, and selectivity, and initiating animal testing. Specifically we will: 1) examine ACTH antagonist structure-activity relationships to increase our understanding of basic structural requirements for the compound to bind to MC2R; 2) assess selectivity and specificity of the ACTH antagonists to other melanocortin and unrelated receptors; (3) assess ADME- related characteristics such as human serum albumin binding, P450 inhibition, lipid membrane, CACO-2 permeability, and in vitro cytotoxicity; 4) perform in vivo animal toxicology/pharmacokinetic testing; and 5) assess ability to block ACTH action in an in vivo animal model. These studies combine ChemDiv's expertise in drug discovery with a Yale laboratory with expertise in GPCR action and treatment of adrenal disorders. The studies will lead to novel approaches for treating patients with ACTH-dependent adrenal disorders. Project Narrative: The production of adrenal gland hormones, including cortisol and androgens, is regulated by pituitary ACTH (adrenocorticotropin hormone), which acts via the melanocortin-2 receptor (MC2R) to stimulate steroid production. Serious clinical disorders affecting the adrenal gland include congenital virilizing adrenal hyperplasia (CAH) and Cushing's disease. The ability to antagonize ACTH action will greatly facilitate the care of these and other conditions affecting the adrenal gland. Unfortunately, high-affinity small molecule ACTH antagonists are not identified yet and are not currently available for clinical use.

描述（申请人提供）：基于MC 2 R拮抗剂的药物开发将直接有益于患有CAH和库欣病的儿童，并将帮助我们了解MC 2 R在代谢途径中的作用。该项目的长期目标是发现MC 2受体的小分子抑制剂，并开发治疗多种代谢性疾病的药物，包括CAH和困扰儿童的库欣病。我们鉴定新型ACTH小分子拮抗剂的I期研究是成功的;我们能够鉴定3种对MC 2 R具有高亲和力的新型非肽类小分子ACTH拮抗剂。这些抑制剂属于具有相似化学骨架的相同化学型。这些化合物是完全的ACTH拮抗剂，有效地抑制ACTH刺激的肾上腺细胞活性。我们已经实现了I期目标，并发现了一系列新的小分子非肽类ACTH拮抗剂。该项目的第二阶段将致力于扩展我们对ACTH拮抗剂的研究，通过使用已鉴定抑制剂的系列类似物来检查结构-活性关系，以评估其ACTH拮抗剂的效力、特异性和选择性，并启动动物试验。具体而言，我们将：1）检查ACTH拮抗剂结构-活性关系以增加我们对化合物结合MC 2 R的基本结构要求的理解; 2）评估ACTH拮抗剂对其它黑皮质素和无关受体的选择性和特异性;（3）评估ADME相关特征，例如人血清白蛋白结合、P450抑制、脂质膜、CACO-2渗透性和体外细胞毒性; 4）进行体内动物毒理学/药代动力学测试;和5）评估在体内动物模型中阻断ACTH作用的能力。这些研究结合了联合收割机化学部在药物发现方面的专业知识和耶鲁大学实验室在GPCR作用和肾上腺疾病治疗方面的专业知识。这些研究将为治疗ACTH依赖性肾上腺疾病患者带来新的方法。项目叙述：肾上腺激素（包括皮质醇和雄激素）的产生受垂体ACTH（促肾上腺皮质激素）调节，ACTH通过黑皮质素-2受体（MC 2 R）刺激类固醇产生。影响肾上腺的严重临床病症包括先天性男性化肾上腺增生（CAH）和库欣病。拮抗促肾上腺皮质激素作用的能力将大大促进这些和其他影响肾上腺的条件的照顾。不幸的是，高亲和力的小分子ACTH拮抗剂尚未被鉴定，并且目前不能用于临床使用。