In vivo probes for the APJ receptor.

APJ 受体的体内探针。

基本信息

批准号：
9095375
负责人：
RANGAN MAITRA
金额：
$ 43.57万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9095375
关键词：
Accounting Adverse effects Affinity Agonist Angiogenic Proteins Angiotensin II Angiotensin Receptor Angiotensins Antihypertensive Agents Biological Assay Biological Markers Blood - brain barrier anatomy Blood Pressure Blood Vessels Blood flow Body mass index Cells Cessation of life Chemicals Complement Complex Coupled Cytochrome P450 Disease Drug Kinetics Elderly Electric Capacitance Enzymes Epidemiology Equilibrium Evaluation Fetus G-Protein-Coupled Receptors Genes Goals Health Heart failure Hepatic Housing Human Hypertension Hypoxia Inflammation Ischemia Knockout Mice Lead Libraries Ligands Link Maternal Age Metabolic Modeling Modification Monitor Nitric Oxide Oral Organ Oxidative Stress Pathway interactions Patients Penetration Peptides Peptidyl-Dipeptidase A Perfusion Pharmaceutical Preparations Placenta Placental Necrosis Placentation Plasma Play Pre-Clinical Model Pre-Eclampsia Pregnancy Property Proteins Publishing Recovery of Function Regulation Renin Renin-Angiotensin System Reporting Resistance Rodent Role Sampling Signal Transduction Smoking Status Sprague-Dawley Rats Symptoms System Testing Therapeutic Vasoconstrictor Agents Vasodilation Woman absorption analog angiogenesis associated symptom cytotoxic design follow-up human disease improved in vitro Assay in vitro Model in vivo in vivo Model insulin sensitivity novel pre-clinical pressure pup radioligand receptor receptor binding release of sequestered calcium ion into cytoplasm reproductive scaffold screening small molecule tool vascular bed

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop and test probes of the apelin (APJ) receptor for in vivo studies related to preeclampsia (PE). Preeclampsia is a complex maternal hypertensive disorder noted in ~7-10% of all pregnancies and accounts for ~100,000 maternal deaths globally each year. Current therapies are inadequate. Preeclampsia is linked to hypertension and inflammation, coupled with impaired vascular endothelial function due to inadequate placentation, and impaired utero-placental perfusion. This results in hypoxia and altered angiogenic balance within the developing fetus. The G-protein coupled receptor (GPCR) protein APJ may play a regulatory role in PE. APJ is activated by circulating but metabolically labile apelin peptides in vivo. APJ is expressed within the vasculature of most organs including placenta. Activation of APJ promotes vasodilation and angiogenesis. Interestingly, APJ knockout (ko) mice suffer from heart failure, demonstrate reduced angiogenic potential, and have reproductive deficiencies (reduced number of pups). Apelin also induces formation of large blood vessels during functional recovery from ischemia, which is a hypoxic and vaso- occlusive disorder like PE. Our published follow-up studies in human patients indicate that the odds of PE are 48% lower for women with high versus low plasma apelin concentration. Past studies also indicate that local apelin and APJ are up-regulated within the placentas of human PE patients perhaps as a compensatory mechanism. Thus, the apelinergic system should be investigated both mechanistically and pharmacologically within the context of PE. However, in vivo studies of APJ are difficult at the moment due to a paucity of available drug-like small molecule ligands of this receptor. To date, our group has made significant progress in this regard. We have developed appropriate assays for APJ and completed a screening campaign to identify hits. These compounds have been refined to produce full-agonist of APJ that are potent (EC50~100 nM). We propose to further refine the drug-like properties of these compounds using iterative synthesis, evaluation, and optimization of drug-like properties using a battery of in vitro assays. Select compounds will undergo pharmacokinetic (PK) testing to identify candidate probes for in vivo testing. We hypothesize that optimized probes of the APJ receptor will produce beneficial anti-hypertensive and pro-angiogenic effects while reducing oxidative stress in preclinical models of PE. Thus, compounds will be evaluated in a well-validated, surgically altered reduced uterine perfusion pressure (RUPP) model of preeclampsia in Sprague Dawley (SD) rats that reproduces several symptoms of the human disease. Blood pressure, angiogenic balance, and oxidative stress related biomarkers will be evaluated. Further, reproductive toxicological analyses will be performed to rule out adverse effects. Successful completion of this project will lead to new in vivo probes of APJ that will enable further studies of this receptor within the context of health and disease.

描述（由适用提供）：该项目的目的是开发和测试与前峰（PE）有关的体内研究的APELIN（APJ）受体的问题。 preeclamsia是一种复杂的孕产妇高血压障碍，在所有怀孕中约7-10％中，全球占约100,000例孕产妇死亡。当前的疗法不足。前环境与高血压和注射有关，并因放置不足而导致的血管内皮功能受损和子宫 - 替代性灌注受损。这会导致缺氧并改变发育中的胎儿内血管生成平衡。 G蛋白偶联受体（GPCR）蛋白APJ可能在PE中起调节作用。 APJ通过体内循环但代谢不稳定的丙酸蛋白肽激活。 APJ在大多数器官的脉管系统中表达，包括plapeta。 APJ的激活促进血管舒张和血管生成。有趣的是，APJ敲除（KO）小鼠患有心力衰竭，表现出降低的血管生成潜力，并且具有生殖缺乏症（幼犬数量减少）。 APELIN还诱导了从缺血恢复功能性恢复期间大型血管的形成，这是PE等低氧和血管闭塞性疾病。我们在人类患者中发表的随访研究表明，高血浆丙蛋白酶浓度的女性的PE几率降低了48％。过去的研究还表明，在人类PE患者的胎盘中，局部APELIN和APJ可能是一种补偿机制。这是应在PE的背景下机械和药物研究的辅助系统。然而，由于该受体的可用药物样小分子配体缺乏，目前对APJ的体内研究很困难。迄今为止，我们的小组在这方面取得了重大进展。我们已经为APJ开发了适当的测定法，并完成了筛选活动以识别命运。这些化合物已被改进，以产生潜在的APJ的全动力（EC50〜100 nm）。我们建议使用迭代合成，评估和使用一系列体外测定的迭代合成，评估和优化这些化合物的药物样特性。选择化合物将接受药代动力学（PK）测试，以识别体内测试的候选问题。我们假设APJ受体的优化问题将产生有益的抗高血压和促血管生成作用，同时减少PE的临床前模型中的氧化应激。这是在Sprague Dawley（SD）大鼠中重现人类疾病的几种症状的Sprague Dawley（SD）大鼠中先兆子痫的子宫灌注压力（RUPP）模型的降低的子宫灌注压力（RUPP）模型中的化合物。将评估血压，血管生成平衡和氧化应激相关的生物标志物。此外，将进行生殖毒理学分析以排除不良影响。该项目的成功完成将导致APJ的新体内问题，这将在健康和疾病的背景下进一步研究该受体。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of a novel small molecule agonist scaffold for the APJ receptor.

DOI：
10.1016/j.bmc.2016.06.018
发表时间：
2016-08-15
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Narayanan S;Maitra R;Deschamps JR;Bortoff K;Thomas JB;Zhang Y;Warner K;Vasukuttan V;Decker A;Runyon SP
通讯作者：
Runyon SP

The complement system and adverse pregnancy outcomes.