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

项目总结 对新的差异化抗高血压疗法的需求显然没有得到满足，因为高血压和它的 尽管已批准了几类药物，但病理性后遗症仍然是人类健康的重大负担。 血管内皮细胞是调节血管紧张素转换酶、炎症、止血和血管的动态界面。 改建。血管内皮功能障碍，包括血管收缩，血管反应性受损， 炎症、血栓形成和血管静息丧失，是许多血管疾病的关键驱动因素。河岸带 药物最近发现了新的小分子，通过激活内皮功能障碍来靶向内皮功能障碍 内皮Krüppel-like factor2(KLF2)通路是血管保护的关键节点。转录因子KLF2是 关键的血管扩张、抗炎、抗凝和体内平衡基因的上游调节因子。KLF2 通过几种介质促进血管扩张和内皮功能，但主要机制是 内皮型一氧化氮合酶基因的反式激活。ENOS及其产品NO被广泛使用 了解血管功能的关键成分，具有血管扩张、抗凝和抗炎作用 效果。我们相信KLF2诱导是一种很有前途的新的治疗方法，对于被广泛研究但仍然存在的 高血压患者一氧化氮生物利用度降低的挑战。我们广泛研究了我们的药理作用 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说 在已建立的高血压大鼠模型中。我们假设KLF2和eNOS是由我们的主要候选人诱导的 将促进血管保护表型，改善内皮功能，降低正常血压 和高血压动物。在这方面的成功将推动该计划进入IND使能研究和临床 评价一种治疗高血压的新方法。

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.