Drug Discovery & Synthesis of Contraceptive Agents

将实施三个男性和两个女性避孕药发现项目，使用最先进的 高通量筛选、基于结构的药物设计和Hit-to-Lead最优化等方法 药物化学：1.男性用H2-甘氨咪唑(H2-GMZ)及其类似物那昔拉辛(NAR) 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精子避孕药，可逆地破坏 EEFIA-肌动蛋白在支持细胞中的捆绑。2.维甲酸受体α(RARpha)作为男性靶标 避孕：RARA(RARA‘’)基因敲除模型和RAR泛拮抗剂的动物实验 已经证实RARpha是确定可逆性男性不育的可行靶点。具有良好口服生物利用度的α选择性RAR拮抗剂的发现有望提供一种比现有泛拮抗剂具有更少不良副作用的男性避孕药。3.CatSper作为男性避孕的靶标：精子的阳离子通道(CatSper)参与了细胞内钙的调节，这是哺乳动物受精过程中启动精子过度运动所必需的重要组成部分。我们的工作假设是，CatSper的抑制剂通过阻止钙离子内流，使精子无法成功穿透卵母细胞并使其受精，从而降低精子的过度运动能力。4.WEE2激酶作为女性避孕的靶标：WEE2的敲除阻止了成熟灵长类卵母细胞的受精，这表明WEE2是开发非激素、配子特异的女性避孕药的一个有前途的靶标。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的药物抑制剂阻止了许多物种的卵母细胞成熟，包括灵长类动物。这些观察结果导致了一种假设，即一种选择性的PDE3A抑制剂可能被开发为女性避孕药。

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.