Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension.

Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia-induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug-enabling studies. © 2023 The Authors.

Citation

Michael S Valentine, Aaron M Bender, Sheila Shay, Krista C Paffenroth, Santhi Gladson, Jonathan W Dickerson, Katherine J Watson, Nicholas J Kapolka, Olivier Boutaud, Jerri M Rook, Timothy S Blackwell, Bryan L Roth, Fiona E Harrison, Eric D Austin, James D West, Craig W Lindsley, W David Merryman. Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension. JACC. Basic to translational science. 2023 Oct;8(10):1379-1388

PMID: 38094686

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