Development of new ADCY10 inhibitors

新型 ADCY10 抑制剂的开发

• 批准号: 10747158
• 负责人: JOCHEN BUCK
• 金额: $ 49.66万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747158
• 关键词: Acute; Adenylate Cyclase; Animal Model; Bicarbonates; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Chemicals; Contraceptive Agents; Contraceptive methods; Cyclic AMP; Data; Development; Dose; Drug Design; Ejaculation; Epididymis; Exhibits; Failure; Female; Fertilization; Fertilization in Vitro; Funding; Genetic; Glaucoma; Goals; Hour; Human; Infertility; Injections; Institution; Kidney Calculi; Kinetics; Knock-out; Knockout Mice; Lead; Male Contraceptive Agents; Male Infertility; Mammalian Oviducts; Measures; Mediating; Medicine; Metaphase; Methods; Molecular; Mouse Strains; Mus; Mutation; Oocytes; Oral Contraceptives; Ovulation; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic Intraocular Pressure; Process; Property; Proteins; Reproductive Physiology; Research; Research Project Grants; Second Messenger Systems; Series; Source; Sperm Motility; Spermatocytes; Sterility; Structure; Swimming; Testing; Therapeutic; Time; Tissues; Travel; cell motility; clinical development; cross reactivity; cytotoxicity; drug discovery; experimental study; high throughput screening; improved; in vivo; inhibitor; lead optimization; loss of function; male; male fertility; men; middle age; molecular modeling; novel; novel therapeutics; pharmacologic; pre-clinical; prevent; reproductive tract; research and development; residence; response; reversible contraceptive; scaffold; sex; side effect; small molecule; sperm cell; sperm function; structural biology; success

Project 3 Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Both processes require soluble adenylyl cyclase (sAC). sAC knockout mice are male specific sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, there are no other immediate phenotypes; thus, an acutely acting sAC inhibitor which blocks sperm functions for hours would be an effective on-demand male contraceptive without eliciting mechanism-based side effects that only manifest when sAC is absent for months or years. Such a male birth control pill would be taken only when, and as often as, needed, shortly before sex. The goal of the Weill Cornell Medicine Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand birth control pills. Project 1 of the WCM-CRC proposes lead optimization of a chemical series already validated in a preclinical animal model. In this Contraception Development Research Project, we propose to develop additional leads, starting from scaffolds structurally distinct from the series optimized in Project 1, into selective, potent, drug-like sAC inhibitors. We propose to leverage our proven workflow of structure-based drug design along with functional testing, to refine these novel chemical scaffolds into inhibitors with increased potency, selectivity, long residence times, and drug-like properties. The ultimate goal of this Project is to develop additional, structurally unrelated, sAC inhibitors as lead compounds to be subjected to the pipeline of refinement cycles and in vivo studies described in other projects of this WCM-CRC.

项目3 精子必须是能动的并完全获能才能使卵母细胞受精。这两个过程都需要 可溶性腺苷酸环化酶（sAC）。sAC敲除小鼠是雄性特异性不育的， 中断sAC是不育的。在小鼠和人中，没有其他直接的表型;因此， 一种有效的sAC抑制剂可以阻断精子功能数小时， 避孕药，而不会引起基于机制的副作用，这些副作用仅在sAC不存在时才表现出来， 数月或数年这种男性避孕药只会在需要的时候服用，而且会在短期内服用 在性行为之前。威尔康奈尔医学避孕研究中心（WCM-CRC）的目标是 将急性作用的sAC抑制剂开发成按需避孕药。WCM-CRC项目1 提出了一个化学系列已经在临床前动物模型中验证的铅优化。在这 避孕发展研究项目，我们建议开发更多的线索，从 支架结构上不同于项目1中优化的系列，成为选择性的，有效的，药物样sAC 抑制剂的我们建议利用我们成熟的基于结构的药物设计工作流程，沿着 功能测试，将这些新的化学支架精制成具有更高效力，选择性， 长的停留时间和类似药物的性质。该项目的最终目标是开发更多的， 结构上不相关的sAC抑制剂作为先导化合物， 本WCM-CRC的其他项目中描述的循环和体内研究。