Identification of Novel ACTH Small Molecule Antagonists

新型 ACTH 小分子拮抗剂的鉴定

• 批准号: 7271167
• 负责人: ILYA OKUN
• 金额: $ 37.34万
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271167
• 关键词: Acute; Adrenal Gland Diseases; Adrenal Gland Hyperfunction; Adrenal Glands; Affect; Affinity; Androgens; Animal Model; Animal Testing; Animals; Artificial Membranes; Autoradiography; Binding; Biological Assay; Caring; Cells; Characteristics; Chemicals; Child; Chronic; Clinical; Condition; Congenital adrenal hyperplasia; Corticotropin; Cushing Syndrome; Cytochrome P450; Development; Disease; Drug Kinetics; Family; G Protein-Coupled Receptor Genes; Goals; Hormone Antagonists; Hormones; Human; Hydrocortisone; In Vitro; Label; Laboratories; Lead; Libraries; Ligand Binding; Lipids; Melanocortin 2 Receptor; Membrane Lipids; Metabolic Diseases; Metabolic Pathway; Mus; Patients; Pattern; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pituitary Gland; Pituitary-dependent Cushing' s disease; Production; Property; Research Personnel; Role; Safety; Series; Serum Albumin; Slice; Small Business Technology Transfer Research; Specificity; Steroid biosynthesis; Steroids; Structure-Activity Relationship; Techniques; Testing; Toxicology; Universities; Vertebral column; adrenal hyperplasia; analog; base; cytotoxicity; drug development; drug discovery; in vivo; inhibitor/antagonist; melanocortin receptor; member; novel; novel strategies; receptor; response; small molecule

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 drug 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 identified three 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（由申请人提供）：基于MC2R拮抗剂的药物开发将直接使患有CAH和库欣病的儿童受益，并将帮助我们了解MC2R在代谢途径中的作用。该项目的长期目标是发现MC2受体的小分子抑制剂，并开发药物治疗包括CAH和库欣病在内的几种代谢性疾病。我们鉴定新型ACTH小分子拮抗剂的I期研究取得了成功；我们能够鉴定出三种新的非肽小分子ACTH拮抗剂，它们对MC2R具有高亲和力。抑制剂具有相似的化学主干，属于相同的化学型。这些化合物是全ACTH拮抗剂，能有效抑制ACTH刺激的肾上腺细胞活性。我们已经达到了I期目标，并发现了一系列新的小分子非肽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，通过使用已识别抑制剂的一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。具体来说，我们将：1)检查ACTH拮抗剂的结构-活性关系，以增加我们对化合物与MC2R结合的基本结构要求的理解；2)评估ACTH拮抗剂对其他黑素皮质素和不相关受体的选择性和特异性；(3)评估ADME相关特征，如人血清白蛋白结合、P450抑制、脂质膜、CACO-2通透性和体外细胞毒性；4)进行体内动物毒理学/药代动力学试验；5)在体内动物模型中评估阻断ACTH作用的能力。这些研究将ChemDiv在药物发现方面的专业知识与耶鲁大学实验室在GPCR作用和肾上腺疾病治疗方面的专业知识结合起来。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。