Identification of Novel ACTH Small Molecule Antagonists

描述(申请人提供)：基于MC2R拮抗剂的药物的开发将直接使患有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，并开发治疗几种代谢性疾病的药物，包括困扰儿童的CAH和库欣病。我们的第一阶段研究成功地发现了新的ACTH小分子拮抗剂；我们能够鉴定出三种与MC2R具有高亲和力的新型非肽类小分子ACTH拮抗剂。这些抑制剂属于相同的化学类型，具有相似的化学骨架。这些化合物是完全的ACTH拮抗剂，可以有效地抑制ACTH刺激的肾上腺细胞活性。我们已经实现了第一阶段的目标，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大我们对ACTH拮抗剂的研究，通过使用已识别的抑制剂的一系列类似物来检查结构-活性关系，以评估它们的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)检测ACTH拮抗剂的构效关系，以增加我们对该化合物与MC2R结合的基本结构要求的了解；2)评估ACTH拮抗剂对其他黑素皮质素和无关受体的选择性和特异性；(3)评估ADME相关特性，如人血清白蛋白结合、P450抑制、脂膜、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；以及5)评估在体动物模型中阻断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的一家实验室结合在一起，后者在GPCR作用和肾上腺疾病的治疗方面具有专业知识。这些研究将为治疗ACTH依赖型肾上腺疾病患者带来新的方法。 项目简介：肾上腺激素的产生，包括皮质醇和雄激素，由垂体ACTH(促肾上腺皮质激素)调节，它通过黑素皮质素-2受体(MC2R)刺激类固醇的产生。影响肾上腺的严重临床疾病包括先天性男性化肾上腺增生症(CAH)和库欣病。拮抗ACTH作用的能力将极大地促进这些和其他影响肾上腺的疾病的护理。不幸的是，高亲和力小分子ACTH拮抗剂还没有被鉴定出来，目前还不能用于临床。

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.