Systemically restricted 5-HT2B antagonists for pulmonary arterial hypertension

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive lethal disease characterized by widespread obstruction in the smallest arteries of the lungs. Pulmonary microvascular obstruction leads to increased pulmonary vascular resistance, which subsequently causes right heart failure. Potential new targets for PAH therapy are lacking, yet despite the existing need for disease-modifying therapeutics, the rational selection of targets is significantly hampered by the still poor understanding of the cellular and molecular mechanisms that mediate PAH pathogenesis. We have shown in multiple animal models of PAH that targeting the serotonin 2B receptor (5- HT2B) genetically and pharmacologically prevents the development of disease. While 5-HT2B antagonism shows tremendous promise for PAH therapy, currently embodiments penetrate the blood-brain barrier. 5-HT2B mutation in the central nervous system is associated with several adverse consequences, such as depression, aggression, impaired sleep, and suicidality that limit the clinical potential of this treatment. Therefore, to overcome this limitation we have developed novel 5-HT2B antagonists that are both selective and potent, but also systemically restricted such that they do not cross the blood-brain-barrier. Here, we propose to de-risk these compounds for clinical translation through lead compound selection, safety and toxicity studies, and finally efficacy in preclinical models. At the conclusion of these aims, we hope to have identified a well-positioned, disease-modifying PAH therapy that has completed IND-enabling studies.