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.
Public Health Relevance Statement: PROJECT NARRATIVE Hypertension imposes a large burden on human health despite therapies available today. Differentiated new therapies are needed to lower blood pressure and prevent the serious complications of hypertension such as heart disease and stroke. Riparian Pharmaceuticals is discovering new therapies targeting the underlying dysfunctional biology of the blood vessels itself to promote vascular health and treat hypertension.
Project Terms: Acetates; Aftercare; After Care; After-Treatment; post treatment; Animals; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antihypertensive Agents; Anti-Hypertensive Agents; Anti-Hypertensive Drugs; Anti-Hypertensives; Antihypertensive Drugs; Antihypertensives; Hypotensive Agent; Hypotensive Drugs; Aorta; Biological Availability; Bioavailability; Biologic Availability; Physiologic Availability; Biology; Blood Vessels; vascular; Deoxycorticosterone; 11-Decorticosterone; 21-Hydroxyprogesterone; Cortexone; Desoxycorticosterone; Desoxycortone; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Endothelium; Vascular Endothelium; Genes; Health; Heart Diseases; Cardiac Diseases; Cardiac Disorders; heart disorder; Hemostatic function; Hemostasis; Human; Modern Man; Hypertension; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; high blood pressure; hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; Inflammation; Mesenteric Arteries; Pharmacology; Phenotype; SHR Rats; Spontaneously Hypertensive Rats; spontaneous hypertensive rat; Inbred SHR Rats; Common Rat Strains; Rat; Rats Mammals; Rattus; social role; Role; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; Stroke; thrombotic disease; thrombotic disorder; Thrombosis; Tissues; Body Tissues; Transactivation; trans-activation; Vascular Diseases; Vascular Disorder; blood vessel disorder; vascular dysfunction; vasculopathy; vasoconstriction; vascular constriction; Vasodilation; Vasodilatation; Vasorelaxation; vascular factor; vascular component; improved; Chemicals; normotensive; analog; Therapeutic; programs; success; BP homeostasis; BP regulation; blood pressure homeostasis; regulate BP; regulate blood pressure; blood pressure regulation; novel; Modeling; protein expression; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; preventing; prevent; ENOS; Endothelial Nitric Oxide Synthase; NOS3; Nitric Oxide Synthase 3; Type III nitric oxide synthase; NOS3 gene; small molecule; Mediator; Mediator of Activation; Mediator of activation protein; Kruppel-like transcription factors; Data; Antiinflammatory Effect; anti-inflammatory effect; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Pathologic; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; hypertension treatment; vascular endothelial dysfunction; Vascular remodeling; Impairment; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; new therapeutic target; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; endothelial dysfunction; blood pressure reduction; BP reduction; lower BP; lower blood pressure; lowers blood pressure; reduce BP; reduce blood pressure; reduction in BP; reduction in blood pressure; Systemic blood pressure; Pharmacology Study; Pharmacological Study; experimental study; experiment; experimental research; lead optimization; lead candidate; primary endpoint; primary end point; hypertensive
