Drug Discovery & Synthesis of Contraceptive Agents

药物发现

• 批准号: 8550538
• 负责人: Gunda I. Georg
• 金额: $ 84.14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8550538
• 关键词: Actins; Adverse effects; Agonist; Animal Experiments; Animal Testing; Animals; Binding; Bioavailable; Biological Assay; Biological Availability; Biological Factors; Bundling; Calcium; Cations; Chemicals; Clinical Trials; Collaborations; Contraceptive Agents; Contraceptive methods; Couples; Development; Drug Design; Drug Kinetics; Enzymes; Female; Female Contraceptions; Female Contraceptive Agents; Fertilization; Funding; Genetic; Germ Cells; Goals; Gonadotropins; Health Sciences; Hormonal; Hormonal Oral Contraceptives; Human; In Vitro; Infertility; Instruction; Kansas; Knock-out; Lead; Macaca; Male Contraceptions; Male Contraceptive Agents; Male Infertility; Marketing; Medical center; Menstrual cycle; Methods; Modeling; Mus; National Institute of Child Health and Human Development; Oocytes; Oral; Oregon; PDE3A gene product; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Pregnancy; Primates; Prodrugs; Property; RXR; Regulation; Research; Research Personnel; Rodent; Specificity; Sperm Motility; Structure; Universities; Vesicle; Water; Woman; Work; analog; base; contraceptive target; design; drug discovery; drug synthesis; high throughput screening; improved; in vivo; inhibitor/antagonist; kinase inhibitor; large scale production; male; medical schools; men; nonhuman primate; novel; oocyte maturation; prevent; programs; retinoic acid receptor alpha; scaffold; screening; sertoli cell; small molecule; sperm cell; virtual

Three male and two female contraceptive drug discovery projects will be pursued, using state-of-the-art methods such as high throughput screening, structure-based drug design, and hit-to-lead optinnization by medicinal chemistry: 1. H2-Gamendazole (H2-GMZ) and Analogues of Narciclasine (NAR) for Male Contraception: The hypothesis of this project is that H2-GMZ and other small molecules such as NAR can be developed as reversible non-hormonal anti-spermatogenic contraceptive agents that reversibly disrupt eEFIA-actin bundling in Sertoli cells. 2. Retinoic Acid Receptor Alpha (RARalpha) as a Target for Male Contraception: Knockout models of RARa (Rara"'") and animal experiments with a RAR pan-antagonist have validated RARalpha as a viable target for establishing reversible male infertility. The discovery of an alpha-selective RAR antagonist with good oral bioavailability is expected to provide a male contraceptive agent that has fewer unwanted side effects than existing pan-antagonists. 3. CATSPER as a Target for Male Contraception: The Cation channel of Sperm (CatSper) is involved in the regulation of intracellular calcium, an important component required for the initiation of sperm hypermotility during mammalian fertilization. Our working hypothesis is that inhibitors of CatSper will reduce sperm hypermotility by preventing Ca2+ influx and rendering sperm unable to successfully penetrate and fertilize the oocyte. 4. WEE2 Kinase as a Target for Female Contraception: Knockdown of WEE2 prevents fertilization of mature primate oocytes, indicating that WEE2 represents a promising target for the development of non-hormonal, gamete-specific contraceptive for women. 5. PDE3A as a Target for Female Contraception: The principal catabolic enzyme in the oocyte is phosphodiesterase 3A (PDE3A). Pharmacologic inhibitors of PDE3A block oocyte maturation in many species, including primates. These observations have led to the hypothesis that a selective PDE3A inhibitor could be developed as a female contraceptive agent.

将利用最先进的技术，开展三个男性和两个女性避孕药物发现项目。 高通量筛选、基于结构的药物设计和领先选择等方法 药物化学：1。H2-格列吡唑（H2-GMZ）和Narciclasine（NAR）类似物用于男性 避孕：该项目的假设是，H2-GMZ和其他小分子如NAR可以 被开发为可逆的非激素抗生精避孕药，可逆地破坏 支持细胞中的eEFIA-肌动蛋白集束。2.视黄酸受体α（RAR α）作为男性的靶点 避孕：RAR α（Rara-1）的敲除模型和使用RAR泛拮抗剂的动物实验 已经验证了RAR α作为建立可逆性男性不育症的可行靶点。具有良好口服生物利用度的α-选择性RAR拮抗剂的发现预期提供比现有的泛拮抗剂具有更少的不希望的副作用的男性避孕剂。3. CATSPER作为男性避孕的靶点：精子阳离子通道（CatSper）参与细胞内钙的调节，细胞内钙是哺乳动物受精过程中启动精子运动过度所需的重要成分。我们的工作假设是CatSper抑制剂将通过阻止Ca 2+内流并使精子无法成功穿透卵母细胞并使其受精来降低精子运动过度。4. WEE 2激酶作为女性避孕的靶点：WEE 2的敲低可阻止成熟灵长类动物卵母细胞的受精，表明WEE 2代表了开发女性非激素、配子特异性避孕药的有希望的靶点。5. PDE 3A作为女性避孕的靶点：卵母细胞中的主要分解代谢酶是磷酸二酯酶3A（PDE 3A）。PDE 3A的药理学抑制剂在许多物种中阻断卵母细胞成熟，包括灵长类动物。这些观察结果导致了这样的假设，即选择性PDE 3A抑制剂可以被开发为女性避孕药。