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的发现扩大了我们对下丘脑-垂体-性腺轴(HPG)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、配子发生和性激素的产生。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罕见和/或经期延长、粉刺、毛发异常生长(由于相关的高雄激素症)、胰岛素抵抗和肥胖。通常，月经异常是青春期发病的信号，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，作为HPG轴和GnRH脉动性的守门人，KISS1R是治疗PCOS神经内分泌疾病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，同时将低雌激素血症的潜在风险降至最低。在我们的第一阶段计划中，我们能够开发药物化学策略和药理学方法学来确定KISS1R拮抗剂的活性。这使得非肽具有良好的效力，并且没有之前发表的唯一一系列拮抗剂的物理化学负担。我们能够扩展我们的第一阶段计划的目标，包括对铅分子的选择性、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在效力、选择性、口服生物利用度(以及其他类似药物的特性)以及在HPG轴控制和脉动性的动物模型中的有效性。如果成功，他的项目将导致选择一种候选药物进行IND前的毒理学研究 支持首个人类研究。最终，这种分子将在后期临床试验中作为治疗多囊卵巢综合征和其他生殖疾病的潜在一流疗法进行评估。

 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.