Drug Discovery & Synthesis of Contraceptive Agents

药物发现

基本信息

批准号：
8700448
负责人：
Gunda I. Georg
金额：
$ 85.17万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/8700448
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

项目摘要

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.

将使用最先进的方法进行三个男性和两个女性避孕药发现项目诸如高吞吐量筛查，基于结构的药物设计和命中率高的方法药物化学：1。H2-gamendazole（H2-GMZ）和含含素的类似物（NAR）避孕：该项目的假设是H2-GMZ和其他小分子（例如NAR）可以被开发为可逆的非激素抗渗透性避孕剂，可逆地破坏 eefia-actin捆绑在Sertoli细胞中。 2。视黄酸受体α（raralpha）作为雄性的靶标避孕：RARA（RARA“'”）的基因淘汰赛和RAR Pan-Antagonist的动物实验已经验证了Raralpha，作为建立可逆男性不育症的可行目标。与现有的泛抗逆势者相比，发现具有良好口服生物利用度良好的α选择性RAR拮抗剂将提供一种男性避孕剂，其不必要的副作用更少。 3。猫作为男性避孕的靶标：精子的阳离子通道（CATSPER）参与细胞内钙的调节，这是哺乳动物受精过程中精子过敏性的重要组成部分。我们的工作假设是，Catsper的抑制剂将通过防止Ca2+涌入和渲染精子无法成功穿透和施肥卵母细胞来减少精子过度的过度。 4。WEE2激酶作为女性避孕的靶标：WEE2的敲低可防止成熟的灵长类动物卵母细胞的受精，这表明WEE2代表了开发非激素，配子特异性避孕药的有希望的目标。 5。PDE3A作为女性避孕的靶标：卵母细胞中的主要分解代谢酶是磷酸二酯酶3A（PDE3A）。 PDE3A的药理学抑制剂在包括灵长类动物在内的许多物种中的卵母细胞成熟。这些观察结果导致了以下假设：选择性PDE3A抑制剂可以作为女性避孕剂发展。