Development of new ADCY10 inhibitors

新型 ADCY10 抑制剂的开发

基本信息

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
项目类别：
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

项目摘要

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 精子必须是运动和完全的电容，才能施肥卵母细胞。两个过程都需要可溶性腺苷酸环化酶（SAC）。 SAC敲除小鼠是男性特异性无菌，男性具有突变的男性干扰囊是不育的。在小鼠和男性中，没有其他直接的表型。因此，一个敏锐的阻塞精子功能数小时的作用囊抑制剂将是一个有效的按需男性避孕药，而没有引起基于机制的副作用，这种副作用仅在缺乏SAC时表现出来几个月或几年。这样的男性避孕药只有在不久的将来和经常需要服用做爱之前。 Weill Cornell医学避孕研究中心（WCM-CRC）的目标是将急性作用的SAC抑制剂发展为按需避孕药。 WCM-CRC的项目1 提出了在临床前动物模型中已经验证的化学系列的铅优化。在这个避孕开发研究项目，我们建议从脚手架在结构上与项目1优化的系列不同，分为选择性，有效，类似药物的囊抑制剂。我们建议利用我们久经考验的基于结构的药物设计的工作流程功能测试，以提高效力，选择性，将这些新型的化学支架完善到抑制剂中长期停留时间和类似毒品的特性。该项目的最终目标是开发其他结构无关的SAC抑制剂作为铅化合物，以进行细化管道在此WCM-CRC的其他项目中描述的周期和体内研究。