Nonpeptide Kisspeptin Antagonists for PCOS and HPG axis control

描述(申请人提供)：在过去的十年中，Kispeptin多肽及其同源受体KISS1R(又名GPR54)的发现扩大了我们对下丘脑-垂体-性腺(HPG)轴的机械理解。Kispeptin系统已被证明是几种生物反馈(内分泌、代谢、昼夜节律)的集成者，并调节GnRH的脉动性分泌，GnRH随后控制促性腺激素LH和FSH的释放。促性腺激素的活性决定了一系列的生物学反应，包括性腺发育、青春期、生育力、配子发生和性激素产生。多囊卵巢综合征(PCOS)是育龄妇女中最常见的激素紊乱。患有多囊卵巢综合征的女性可能会出现月经不频繁和/或经期延长、毛发异常生长(由于相关的高雄激素症)、粉刺和肥胖。通常情况下，月经异常预示着青春期的状况，尽管多囊卵巢综合征可能会在原因不明的体重增加和/或怀孕困难之后表现出来。目前的治疗方法依赖于控制疾病的症状，而不是病因。最近的证据表明，PCOS病理的一个特征是GnRH分泌的高度脉动性。因此，KISS1R作为HPG轴和GnRH信号的守门人，是治疗PCOS的一个有吸引力的新机制。KISS1R拮抗剂应该抑制GnRH的搏动性，并提供在下丘脑水平治疗该疾病的第一个可能性。 到目前为止，还没有KISS1R的药物样非肽调节剂。我们的第一阶段方法是开发药理工具，并将它们部署在体外测试级联中，以发现和表征KISS1R的类药物、非肽拮抗剂。这一分析级联将使用不同的分析方法(例如，全细胞功能分析、竞争结合分析)，以便我们能够快速评估非肽化合物，并识别那些表现出难以克服的拮抗作用和较慢的受体解离速度的化合物。我们将使用这些信息来指导小分子药物化学努力来表征类药物铅化学系列。我们先前已经证明，使用这种类型的级联来指导药物化学努力可以绕过许多经常导致早期计划误入歧途的常见问题。如果成功，该项目将为第二阶段优化(药代动力学、药效学和毒理学)和临床前开发一组新的KISS1R拮抗剂铺平道路，这些拮抗剂能够为治疗多囊卵巢综合征和潜在的其他生殖疾病的人类临床开发做好准备。 公共卫生相关性：该项目需要开发Kispeptin受体分析，用于指导设计和合成治疗多囊卵巢综合征(PCOS)的新型类药物化合物。如果成功，这项工作将提供可优化用于人体临床试验的先导分子。

DESCRIPTION (provided by applicant): During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R (aka GPR54) 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, aberrant hair growth (due to associated hyperandrogenism), acne and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals 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 signaling, KISS1R is an attractive new mechanism for treating the cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level. To date there are no drug-like, nonpeptide modulators of KISS1R. Our Phase I approach is to develop the pharmacological tools and deploy them in an in vitro assay cascade for the discovery and characterization of drug-like, nonpeptide antagonists of KISS1R. This assay cascade will employ different assays (e.g. whole cell functional, competition binding) such that we will be able to rapidly evaluate nonpeptide compounds and identify those that display insurmountable antagonism and slow dissociation rates from the receptor. We will use this information to guide small molecule medicinal chemistry efforts to characterize a drug-like lead chemical series. We have previously demonstrated that the use of this type of cascade to guide medicinal chemistry efforts can circumvent many common issues that often lead early stage programs astray. If successful, this project will pave the way for the Phase II optimization (pharmacokinetic, pharmacodynamic, and toxicological) and preclinical development of a novel set of KISS1R antagonists capable of being ready for human clinical development for the treatment of PCOS and potentially other reproductive disorders. PUBLIC HEALTH RELEVANCE: This project entails the development of kisspeptin receptor assays that will be used to guide design and synthesis of novel drug-like compounds for the treatment of polycystic ovary syndrome (PCOS). If successful, this work will provide lead molecules that could be optimized for human clinical trials.