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

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

doi:10.1016/j.jacbts.2023.06.014

Development of a Peripherally Restricted 5-HT_2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension

JACC Basic Transl Sci. 2023 Sep 13;8(10):1379-1388. doi: 10.1016/j.jacbts.2023.06.014. eCollection 2023 Oct.

Authors

Michael S Valentine¹, Aaron M Bender², Sheila Shay³, Krista C Paffenroth⁴, Santhi Gladson³, Jonathan W Dickerson², Katherine J Watson², Nicholas J Kapolka⁵, Olivier Boutaud², Jerri M Rook², Timothy S Blackwell³, Bryan L Roth⁵, Fiona E Harrison⁶, Eric D Austin³, James D West³, Craig W Lindsley², W David Merryman¹

Affiliations

¹ Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
² Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
³ Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
⁵ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁶ Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Abstract

Ligands for the serotonin 2B receptor (5-HT_2B) 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-HT_2B. 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-HT_2B 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-HT_2B ligands with high potency and selectivity for the 5-HT_2B receptor subtype. Next-generation 5-HT_2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug-enabling studies.

Keywords: drug development; peripherally restricted; pulmonary arterial hypertension; serotonin.

Grants and funding

R35 HL135790/HL/NHLBI NIH HHS/United States