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: 8308166
• 负责人: Stephen F Betz
• 金额: $ 29.63万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308166
• 关键词: Acne; Address; Adolescence; Affinity; Age; Binding; Biological; Biological Assay; Biological feedback; Cells; Characteristics; Chemicals; Circadian Rhythms; Clinical; Clinical Treatment; Clinical Trials; Defect; Development; Disease; Dissociation; Drug Kinetics; Endocrine; Equilibrium; Evaluation; Fertility; Gametogenesis; Gatekeeping; Goals; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Government; Growth; Hair; Hormonal; Hour; Human; Hyperandrogenism; Hypothalamic structure; In Vitro; KISS1R gene; Kinetics; Lead; Legal patent; Ligand Binding; Ligands; Literature; Membrane; Menstruation; Metabolic; Obesity; Pathology; Peptides; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Polycystic Ovary Syndrome; Preparation; Production; Property; Puberty; Reporting; Second Messenger Systems; Series; Signal Transduction; Staging; Stream; Structure; Symptoms; System; Toxicology; Weight Gain; Woman; Work; base; clinical application; controlled release; design; endometriosis; hypothalamic pituitary gonadal axis; in vitro Assay; in vivo; kisspeptin; novel; peptide analog; pharmacophore; pituitary gonadal axis; pre-clinical; pregnant; programs; receptor; reproductive; reproductive hormone; research clinical testing; response; second messenger; small molecule; success; therapy development; tool; Acne; Address; Adolescence; Affinity; Age; Binding; Biological; Biological Assay; Biological feedback; Cells; Characteristics; Chemicals; Circadian Rhythms; Clinical; Clinical Treatment; Clinical Trials; Defect; Development; Disease; Dissociation; Drug Kinetics; Endocrine; Equilibrium; Evaluation; Fertility; Gametogenesis; Gatekeeping; Goals; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Government; Growth; Hair; Hormonal; Hour; Human; Hyperandrogenism; Hypothalamic structure; In Vitro; KISS1R gene; Kinetics; Lead; Legal patent; Ligand Binding; Ligands; Literature; Membrane; Menstruation; Metabolic; Obesity; Pathology; Peptides; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase II Clinical Trials; Polycystic Ovary Syndrome; Preparation; Production; Property; Puberty; Reporting; Second Messenger Systems; Series; Signal Transduction; Staging; Stream; Structure; Symptoms; System; Toxicology; Weight Gain; Woman; Work; base; clinical application; controlled release; design; endometriosis; hypothalamic pituitary gonadal axis; in vitro Assay; in vivo; kisspeptin; novel; peptide analog; pharmacophore; pituitary gonadal axis; pre-clinical; pregnant; programs; receptor; reproductive; reproductive hormone; research clinical testing; response; second messenger; small molecule; success; therapy development; tool

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.

描述（由申请人提供）：在过去的十年中，Kisspeptin肽的发现及其同源受体Kiss1r（又名GPR54）扩大了我们对催眠丘脑 - 垂体 - 高核（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，配子发生和性激素的产生。多囊卵巢综合征（PCOS）是生殖年龄妇女中最常见的激素疾病。在患有PCOS的女性中，可能出现罕见和/或长时间的月经期，异常的头发生长（由于相关的超雄激素），痤疮和肥胖症。通常，月经异常标志着青春期的状况，尽管PCOS可能在无法解释的体重增加和/或难以怀孕后表现出来。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。因此，作为HPG轴和GNRH信号传导的“守门人”，Kiss1r是一种有吸引力的新机制来治疗PCOS的原因。 KISS1R拮抗剂应抑制GNRH的搏动性，并提供下丘脑水平治疗该疾病的第一个可能性。 迄今为止，没有类似毒品的Kiss1r的非肽调节剂。我们的I阶段方法是开发药理学工具，并将其部署在体外测定级联反应中，以发现和表征kiss1r的类似药物的非肽拮抗剂。该测定的级联反应将采用不同的测定（例如全细胞功能，竞争结合），以便我们能够快速评估非肽化合物并识别那些表现出无法克服的拮抗作用和与受体分离速度缓慢的分离率的化合物。我们将使用此信息来指导小分子药物化学工作，以表征类似药物的铅化学系列。我们以前已经证明，使用这种级联反应指导药物化学工作可以避免许多常见的问题，这些问题通常会导致早期阶段误入歧途。如果成功的话，该项目将为II期优化（药代动力学，药效学和毒理学）和临床前开发铺平道路。 公共卫生相关性：该项目需要开发Kisspeptin受体测定法，该测定方法将用于指导新型药物样化合物的设计和合成，用于治疗多囊卵巢综合征（PCOS）。如果成功，这项工作将提供可以针对人类临床试验进行优化的铅分子。