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

• 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
• 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

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.

项目摘要 对于新的差异化抗高血压疗法存在明显未满足的需求，因为高血压及其 尽管有几类批准的药物，病理学后遗症仍然是人类健康的重大负担。 血管内皮是调节血管紧张素、炎症、止血和血管生成的动态界面。 重塑血管内皮功能障碍，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血管疾病的关键驱动因素。河岸 制药公司最近发现了新的小分子，通过激活内皮细胞， 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、抗凝和稳态基因的上游调节因子。KLF2 通过几种介质促进血管舒张和内皮功能，但主要机制是 内皮型一氧化氮合酶（eNOS）基因的反式激活。eNOS及其产物NO广泛应用于 具有血管舒张、抗凝血和抗炎作用的血管功能的关键成分 方面的影响.我们相信KLF2诱导是一种有前途的新的治疗方法，广泛研究，但持续 高血压患者NO生物利用度降低的挑战。我们已经广泛研究了我们的药理学 一流的KLF2诱导治疗方案在这个项目中，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。我们假设，我们的主要候选人KLF2和eNOS的诱导， 将促进血管保护表型，改善内皮功能，降低血压正常者的血压 高血压动物这里的成功将推动该计划进入IND使能研究和临床 评价一种新的治疗高血压的方法。