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（由申请人提供）：该项目的目标是开发和测试 apelin (APJ) 受体探针，用于与先兆子痫 (PE) 相关的体内研究。先兆子痫是一种复杂的孕产妇高血压疾病，发病率约为 7-10%。每年，全球约有 100,000 名孕产妇死亡，目前的治疗方法不足，导致先兆子痫与高血压和炎症以及血管受损有关。由于胎盘形成不足和子宫胎盘灌注受损，导致发育中的胎儿缺氧和血管生成平衡改变。G 蛋白偶联受体 (GPCR) 蛋白 APJ 可能在 PE 中发挥调节作用。体内循环但代谢不稳定的 apelin 肽在包括胎盘在内的大多数器官的脉管系统中表达。众所周知，APJ 敲除 (ko) 小鼠患有心力衰竭，血管生成潜力降低，并且具有生殖缺陷（幼仔数量减少），Apelin 还会在缺血（缺氧和缺氧）功能恢复过程中诱导大血管的形成。我们发表的对人类患者的后续研究表明，与血浆 apelin 浓度低的女性相比，PE 的几率要低 48%。 apelin 和 APJ 在人类 PE 患者的胎盘中上调，这可能是一种补偿机制，因此，应该在 PE 的背景下对 apelingic 系统进行机制和药理学研究。然而，目前 APJ 的体内研究很困难。由于缺乏该受体的药物样小分子配体，迄今为止，我们的团队在这方面已经取得了重大进展，我们已经开发出适当的 APJ 检测方法，并完成了筛选活动以识别命中。这些化合物经过精炼，可产生有效的 APJ 全激动剂（EC50~100 nM），我们建议通过迭代合成、评估和优化药物样特性来进一步精炼这些化合物的药物样特性。我们对选定的化合物进行药代动力学 (PK) 测试，以确定用于体内测试的候选探针，从而发现 APJ 受体的优化探针将产生有益的抗高血压和促血管生成作用，同时减少氧化。因此，将在经过充分验证的、经过手术改变的先兆子痫 (RUPP) 模型中对化合物进行评估，该模型再现了人类疾病的几种症状。此外，还将评估血管生成平衡和氧化应激相关的生物标志物，以排除不良影响。 APJ 将使在健康和疾病背景下进一步研究该受体成为可能。

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.

发现 APJ 受体的新型小分子激动剂支架。

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

Regulation of the Apelinergic System and Its Potential in Cardiovascular Disease: Peptides and Small Molecules as Tools for Discovery.

肾上腺能系统的调节及其在心血管疾病中的潜力：肽和小分子作为发现工具。