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（由申请人提供）：在过去的十年中，Kisspeptin 肽及其同源受体 KISS1R 的发现扩展了我们对下丘脑-垂体-性腺 (HPG) 轴的机制的理解。 Kisspeptin 系统已被证明是一个整合器。多种生物反馈流（内分泌、代谢、昼夜节律）并调节 GnRH 的脉冲式分泌，随后控制促性腺激素 LH 和 FSH 的释放，决定一系列生物反应，包括性腺发育、青春期、生育力、配子发生和性激素产生，多囊卵巢综合症 (PCOS) 是女性中最常见的激素紊乱。月经周期少和/或延长、痤疮、毛发生长异常（由于相关的雄激素过多症）、胰岛素抵抗和肥胖都可能发生。对于患有多囊卵巢综合症的女性来说，月经异常通常是青春期发病的信号，但多囊卵巢综合症可能会在不明原因的体重增加和/或怀孕困难后出现，目前的治疗依赖于控制疾病的症状而不是病因。有证据表明，PCOS 病理学的一个标志是 GnRH 分泌的过度搏动，因此，作为 HPG 轴和 GnRH 搏动的“看门人”，KISS1R 是一种有吸引力的新产品。 KISS1R 拮抗剂应抑制 GnRH 搏动，并提供在下丘脑水平治疗该疾病的第一个可能性，同时最大限度地降低低雌激素血症的潜在风险。化学策略和药理学方法来确定 KISS1R 拮抗剂的活性，这产生了具有良好效力的非肽，并且没有之前唯一系列的理化责任。我们能够扩展第一阶段计划的目标，包括先导分子的选择性、药代动力学和药效学的初步表征，我们的第二阶段计划是利用药理学、受体结构模型和药物化学来进一步开发。这些拮抗剂的效力、选择性、口服生物利用度（以及其他药物样特性）以及 HPG 轴控制和搏动动物模型中的功效如果成功，他的项目将导致选择一种药物。预 IND 候选药物使毒理学研究能够 最终，该分子将在后期临床试验中作为治疗多囊卵巢综合症和其他生殖疾病的潜在一流疗法进行评估。