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H2-Gamendazole analogues as reversible non-hormonal male contraceptive agents

H2-甘孟唑类似物作为可逆非激素男性避孕药

基本信息

批准号：
8692993
负责人：
JOSEPH S TASH
金额：
$ 25.46万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692993
关键词：
Actins Address Adult Adverse effects Apical Behavior Binding Binding Sites Bioavailable Biological Assay Biological Availability Biological Markers Blood Budgets Bundling Cells Chemicals Clinical Trials Contraceptive Agents Data Decision Making Development Dose Drug Kinetics Ensure Environment F-Actin Family Planning Fertility Funding Goals Health Human In Vitro Infertility Instruction Link Macaca mulatta Male Contraceptive Agents Monitor Oral Partner in relationship Personal Satisfaction Pharmaceutical Chemistry Pharmaceutical Preparations Post-Translational Protein Processing Pregnancy Process Proteins Protocols documentation Rattus Recovery Resources Rest Safety Seminal fluid Signal Pathway Signal Transduction Signaling Protein Site Sperm Count Procedure Spermatids Spermiogenesis Structural Protein Testicular Hormones Testing Toxicology United States National Institutes of Health Woman Work analog base clinical toxicology contraceptive target design high throughput screening in vivo inhibitor/antagonist light scattering male men mutant nonhuman primate novel pre-clinical premature programs protein protein interaction protein structure reproductive research and development scaffold sertoli cell small molecule src-Family Kinases success three dimensional structure uptake virtual

项目摘要

In the previous U54 funding period, we focused on developing a class of novel snnall molecule oral nonhormonal anti-spermatogenic contraceptive agents. Of these, H2-gamendazole (H2-GMZ) is now identified as most promising, with 100% oral bioavailability, and 100% infertility followed by 100% recovery of fertility in rats, with no loss in mating behavior. Pilot proof-of-concept studies in non-human primates showed completely reversible declines in spermatid count and semen sperm count with no adverse side effects. H2-GMZ is rapidly absorbed by Sertoli cells and appears to cause premature release of spermatids via binding to and disruption of the eEF1A-F-actin-bundles associated with the apical ectoplasmic specializations. An alternative compound, narciclasine (NAR), has also been identified with similar disruptive effects on the non canonical eEF1A-actin bundling function in Sertoli cells. In order to achieve the overall goal of moving H2 GMZ towards FDA IND status and clinical trials, critical efficacy data in non-human primates, elaborate all of the steps in the mechanism of action of H2-GMZ, and prudent discovery of alternative chemical leads are needed. Thus, the overall hypothesis for this project is that H2-GMZ and other small molecules that reversibly disrupt eEFIA-actin bundling in Sertoli cells can be developed as clinically useful reversible anti-spermatogenic contraceptive agents. Three specific aims are proposed to achieve these goals: Aim 1: Determine proof-of concept efficacy and pharmacokinetics of oral low-dose H2-GMZ as a reversible anti-spermatogenic contraceptive agent in non-human primates. Aim 2: Determine the mechanism of H2-GI\/IZ and novel small molecule-elicited changes in eEF1A actinbundling and post-translational modification on premature loss of spermatids. Aim 3: Identify and optimize other novel selective small molecules that mimic H2-GMZ-eEF1A actions as anti- spermatogenic contraceptive agents. Success in these endeavors will provide essential data needed to enable ultimately moving H2-GMZ into pre-clinical toxicology and registration as an FDA IND for the start of clinical trials in humans.

在之前的U54资助期内，我们重点开发了一类新型小分子口服非激素药物