New Drugs for Stress-related Affective Illness

治疗压力相关情感疾病的新药

• 批准号: 8300805
• 负责人: Michael J Brownstein
• 金额: $ 59.53万
• 依托单位: AZEVAN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300805
• 关键词: Adrenal Glands; Adverse effects; Affect; Affective; American; Animal Model; Anterior Pituitary Gland; Back; Behavioral Assay; Binding; Biological; Biological Availability; Biology; Chronic; Chronic stress; Depressed mood; Development; Disease; Economic Burden; Funding; Housing; Human; Hypothalamic structure; Individual; Industry; Investments; Limbic System; Mental Depression; Metabolism; Mood Disorders; Oral; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phase; Pituitary Gland; Private Sector; Psychological Stress; Public Health; Regulation; Small Business Innovation Research Grant; Social Behavior; Staging; Stress; Structure; Therapeutic; Toxic effect; Toxicology; Vasopressin Antagonist; Vasopressins; Work; base; commercialization; drug candidate; drug development; hypothalamic-pituitary-adrenal axis; improved; in vitro activity; neuroadaptation; next generation; novel; novel therapeutics; pre-clinical; programs; public health relevance; receptor

DESCRIPTION (provided by applicant): Vasopressin (AVP) antagonists represent a novel therapeutic class for the treatment of depression. The potential utility of these compounds has emerged from observations in depressed individuals, findings in animal models, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. This Fast Track proposal seeks support for the identification of novel mixed vasopressin 1a/1b (V1a/V1b) receptor antagonists and the preclinical development of recently discovered molecules in this class that already demonstrate excellent biological activity in vitro. The scientific basis for mixed V1a/V1b antagonists as a pharmacotherapy for depression includes: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of depression, 2) recognition that AVP, not CRF, drives HPA function associated with chronic psychological stress, and 3) the localization of V1a and V1b receptors in regions involved in the control of social behaviors and HPA axis regulation (V1a in limbic system; V1b in limbic system and anterior pituitary). The initial development of these mixed antagonists to date has been supported by private sector venture funding. SBIR Fast Track support will enable essential preclinical development work that will advance candidate molecules to the stage where bulk synthesis and IND-enabling toxicology can be undertaken. Bringing candidates to this status will accelerate commercialization opportunities by significantly enhancing the likelihood of additional private financial investment or a co-development partnership structure with a major pharmaceutical house. PUBLIC HEALTH RELEVANCE: The public health need for new pharmaceutical treatments for depression is well documented. Depression affects some 20 million Americans each year and carries a conservatively estimated annual total economic burden of $125 billion. Existing drugs for depression are not uniformly effective, frequently have undesirable side effects, and do not help some 50% of individuals suffering from the disorder according to recent estimates. These limitations demonstrate that a new treatment approach through mixed V1a/V1b receptor antagonism may offer a significant opportunity for improved outcomes with substantial societal benefit.

描述（由申请人提供）：加压素（AVP）拮抗剂代表了治疗抑郁症的新型治疗类别。这些化合物的潜在用途已经从对抑郁个体的观察、动物模型的发现以及对慢性压力下下丘脑-垂体-肾上腺（HPA）轴调节变化的了解中显现出来。该快速通道提案寻求支持新型混合加压素 1a/1b (V1a/V1b) 受体拮抗剂的鉴定以及最近发现的此类分子的临床前开发，这些分子已在体外表现出优异的生物活性。混合 V1a/V1b 拮抗剂作为抑郁症药物疗法的科学依据包括：1) 在受影响的人类和抑郁症动物模型中，伴随慢性压力的 HPA 功能的神经适应和失调，2) 认识到 AVP（而不是 CRF）驱动 HPA与慢性心理压力相关的功能，以及 3) V1a 和 V1b 受体在参与社会行为控制和 HPA 轴调节的区域中的定位（边缘系统中的 V1a； V1b 位于边缘系统和垂体前叶）。迄今为止，这些混合拮抗剂的初步开发得到了私营部门风险投资的支持。 SBIR 快速通道支持将实现重要的临床前开发工作，将候选分子推进到可以进行批量合成和支持 IND 毒理学的阶段。使候选人达到这一地位将显着提高额外私人金融投资或与大型制药公司共同开发合作伙伴关系结构的可能性，从而加速商业化机会。 公共卫生相关性：公共卫生对抑郁症新药物治疗的需求是有据可查的。抑郁症每年影响约 2000 万美国人，保守估计每年造成的经济负担高达 1250 亿美元。根据最近的估计，现有的治疗抑郁症的药物效果并不统一，经常有不良副作用，并且对大约 50% 的抑郁症患者没有帮助。这些局限性表明，通过混合 V1a/V1b 受体拮抗作用的新治疗方法可能为改善结果提供重要机会，并带来巨大的社会效益。