Pharmacological induction of KLF2 and reversal of endothelial dysfunction for the treatment of hypertension

KLF2 的药理诱导和内皮功能障碍的逆转治疗高血压

基本信息

批准号：
10484143
负责人：
William James Adams
金额：
$ 31.07万
依托单位：
RIPARIAN PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484143
关键词：
Acetates Aftercare Animals Anti-Inflammatory Agents Antihypertensive Agents Antiinflammatory Effect Aorta Biological Availability Biology Blood Vessels Chemicals Data Deoxycorticosterone Development Endothelium Genes Health Heart Diseases Hemostatic function Human Hypertension Impairment Inbred SHR Rats Inflammation Kruppel-like transcription factors Mediator of activation protein Mesenteric Arteries Modeling NOS3 gene Pathologic Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Phenotype Rattus Role Stroke Systemic blood pressure Therapeutic Thrombosis Tissues Transactivation Vascular Diseases Vascular Endothelium Vascular remodeling Vasodilation analog blood pressure reduction blood pressure regulation endothelial dysfunction experimental study hypertension treatment hypertensive improved lead candidate lead optimization new therapeutic target normotensive novel novel therapeutic intervention novel therapeutics pre-clinical prevent primary endpoint programs protein expression research clinical testing small molecule success vascular endothelial dysfunction vascular factor vasoconstriction

项目摘要

PROJECT SUMMARY There is a clear unmet need for new differentiated anti-hypertensive therapies, as high blood pressure and its pathological sequelae remain significant burdens to human health despite several classes of approved drugs. The vascular endothelium is a dynamic interface that regulates vasotone, inflammation, hemostasis and vascular remodeling. Dysfunction of the vascular endothelium, including vasoconstriction, impaired vasoreactivity, inflammation, thrombosis and loss of vascular quiescence, is a key driver of many vascular diseases. Riparian Pharmaceuticals recently discovered novel small molecules that target endothelial dysfunction by activating the endothelial Krüppel-like factor 2 (KLF2) pathway, a key node of vasoprotection. The transcription factor KLF2 is an upstream regulator of critical vasodilatory, anti-inflammatory, anti-coagulatory and homeostatic genes. KLF2 promotes vasodilation and endothelial function by several mediators but a principal mechanism is the transactivation of the endothelial nitric oxide synthase (eNOS) gene. eNOS and its product NO are widely appreciated key components of vascular function having vasodilatory, anti-coagulatory and anti-inflammatory effects. We believe KLF2 induction is a promising new therapeutic approach to the widely studied but persistent challenge of reduced NO bioavailability in hypertension. We have extensively studied the pharmacology of our first-in-class KLF2-inducing therapeutic program. In this project, we plan to validate our therapeutic hypothesis in established hypertensive rat models. We hypothesize that KLF2 and eNOS induction by our lead candidate will promote a vasoprotective phenotype, improve endothelial function and lower blood pressure in normotensive and hypertensive animals. Success here will advance this program into IND-enabling studies and clinical evaluation of a new therapeutic approach to hypertension.

项目概要由于高血压及其相关疾病，对新的差异化抗高血压疗法的需求显然尚未得到满足。尽管有几类已获批准的药物，但病理后遗症仍然对人类健康造成重大负担。血管内皮是调节血管紧张素、炎症、止血和血管的动态界面。血管内皮重塑功能障碍，包括血管收缩、血管反应性受损，炎症、血栓形成和血管静止丧失是许多河岸疾病的关键驱动因素。制药公司最近发现了新型小分子，可通过激活内皮功能障碍来治疗内皮功能障碍。内皮Krüppel样因子2（KLF2）通路，血管保护的关键节点转录因子KLF2是。关键血管舒张、抗炎、抗凝血和稳态基因的上游调节因子。通过多种介质促进血管舒张和内皮功能，但主要机制是内皮一氧化氮合酶（eNOS）基因的反式激活及其产物NO广泛存在。赞赏血管功能的关键成分具有血管舒张、抗凝和抗炎作用我们相信 KLF2 诱导是一种有前途的新治疗方法，已被广泛研究但持久。高血压中NO生物利用度降低的挑战我们主要研究了我们的药理学。一流的 KLF2 诱导治疗计划在这个项目中，我们计划验证我们的治疗假设。在已建立的高血压大鼠模型中，我们勇敢地使用我们的主要候选者诱导 KLF2 和 eNOS。将促进血管保护表型，改善内皮功能并降低正常血压下的血压和高血压动物。这里的成功将推动该项目进入 IND 支持的研究和临床。评估高血压的新治疗方法。