Nonpeptide Kisspeptin Antagonists for PCOS and HPG axis control

用于 PCOS 和 HPG 轴控制的非肽 Kisspeptin 拮抗剂

• 批准号: 8833091
• 负责人: Stephen F Betz
• 金额: $ 78.38万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833091
• 关键词: Abbreviations; Acne; Address; Adolescence; Age; Animal Model; Bibliography; Binding; Biological; Biological Assay; Biological Availability; Biological feedback; Characteristics; Circadian Rhythms; Clinical; Clinical Trials; Communities; Defect; Detection; Development; Disease; Dose; Drug Kinetics; Endocrine; Ensure; Enzymes; Evaluation; Fertility; Gametogenesis; Gatekeeping; Goals; Gonadal Steroid Hormones; Gonadotropins; Government; Growth; Hair; Hormonal; Human; Hyperandrogenism; Hypothalamic structure; In Vitro; Insulin Resistance; Intravenous; Ion Channel; KISS1 gene; Lead; Maximum Tolerated Dose; Menstruation; Metabolic; Methodology; Modeling; Mus; Neurosecretory Systems; Obesity; Oral; Pathology; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Pituitary Gland; Polycystic Ovary Syndrome; Preparation; Production; Property; Puberty; Publishing; Rattus; Research; Risk; Rodent; Safety; Series; Signal Transduction; Staging; Stream; Structural Models; Symptoms; System; Testing; Toxic effect; Toxicology; Weight Gain; Woman; Work; clinical application; controlled release; drug candidate; hypothalamic pituitary gonadal axis; improved; in vivo; innovation; kisspeptin; novel; novel therapeutics; pharmacodynamic model; pituitary gonadal axis; pre-clinical; pregnant; programs; public health relevance; receptor; reproductive; reproductive axis; reproductive hormone; research clinical testing; response; stable cell line; success; targeted treatment; tool; treatment strategy

 DESCRIPTION (provided by applicant): During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R has expanded our mechanistic understanding of the hypthothalamic-pituitary-gonadal (HPG) axis. The kisspeptin system has been shown to be an integrator of several streams of biological feedback (endocrine, metabolic, circadian) and regulates the pulsatile secretion of GnRH, which subsequently controls the release of the gonadotropins LH and FSH. Gonadotropin activity dictates a host of biological responses, including gonadal development, puberty, fertility, gametogenesis, and sex hormone production. Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women of reproductive age. Infrequent and/or prolonged menstrual periods, acne, aberrant hair growth (due to associated hyperandrogenism), insulin resistance, and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals the onset of the condition in adolescence, though PCOS may manifest later following unexplained weight gain and/or difficulty becoming pregnant. Current treatments rely on managing the symptoms of the disease rather than the cause. Recent evidence demonstrates that a hallmark of the pathology of PCOS is hyperpulsatility of GnRH secretion. Thus, as the "gatekeeper" of the HPG-axis and GnRH pulsatility, KISS1R is an attractive new mechanism for treating the neuroendocrine cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level, while minimizing the potential risk of hypoestrogenemia. During our Phase I program, we were able to develop the medicinal chemistry strategy and pharmacologic methodology to determine the activity of KISS1R antagonists. This resulted in non-peptides with good potency and none of the physicochemical liabilities of the only series of previously published antagonists. We were able to extend the goals of our Phase I program to include an initial characterization of selectivity, pharmacokinetics, and pharmacodynamics of a lead molecule. Our Phase II plan is to use pharmacology, receptor structural models and medicinal chemistry to further develop these antagonists in terms of potency, selectivity, oral bioavailability (as well as other drug-like properties), and efficacy in animal models of HPG axis control and pulsatility. If successful, his project will result in the selection of a drug candidate for pre-IND enabling toxicology studies to support first-in-human studies. Ultimately, this molecule would be evaluated in later stage clinical trials as a potential First-In-Class treatment for women with PCOS and other reproductive disorders.

 描述（由适用提供）：在过去的十年中，亲吻蛋白辣椒及其同源受体Kiss1r的发现扩大了我们对催眠丘脑 - 垂体 - 基达尔（HPG）轴的机械理解。吻肽系统已被证明是几种生物反馈流（内分泌，代谢，昼夜节律）的积分器，并调节了GnRH的脉动分泌，后来控制了促性腺激素LH和FSH的释放。促性腺激素活性决定了许多生物学反应，包括性腺发育，青春期，生育能力，配子发生和性马酮产生。多囊卵巢综合征（PCOS）是生殖年龄妇女中最常见的骑马疾病。在患有PCOS的女性中，可能会发生不频繁和/或长时间的月经期，痤疮，异常的头发生长（由于相关的超雄激素），胰岛素抵抗和肥胖症。通常，月经异常标志着青春期病情的发作，尽管PCOS可能会在意外的体重增加和/或困难怀孕后稍后表现出来。当前的治疗依赖于管理疾病的症状而不是原因。最近的证据表明，PCOS病理学的标志是GNRH分泌的螺栓过度。作为HPG轴和GNRH搏动性的“看门人”，Kiss1r是一种有吸引力的新机制，用于治疗PCOS的神经内分泌原因。 KISS1R拮抗剂应该死的GNRH搏动性，并提供在下丘脑水平治疗该疾病的第一个可能性，同时最大程度地减少了低雌激素血症的潜在风险。在我们的第一阶段计划中，我们能够制定药物化学策略和药物学方法，以确定KISS1R拮抗剂的活性。这导致了具有良好效力的非肽，并且没有唯一一系列先前发表的拮抗剂的物理责任。我们能够扩展I阶段计划的目标，以包括铅分子的选择性，药代动力学和药效学的初始表征。我们的II期计划是使用药理学，受体结构模型和药物化学，以进一步发展这些拮抗剂，以效力，选择性，口服生物利用度（以及其他类似药物样的特性），并在HPG轴控制和脉动性动物模型中有效。如果成功的话，他的项目将导致选择候选药物，以使毒理学研究能够进行毒理学研究 支持首先人类研究。最终，该分子将在后期临床试验中评估，作为对PCOS和其他生殖疾病女性的潜在一流治疗方法。