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Development of a Peripherally Restricted 5-HT2B Partial Agonist for Treatment of Pulmonary Arterial Hypertension.
Valentine, Michael S; Bender, Aaron M; Shay, Sheila; Paffenroth, Krista C; Gladson, Santhi; Dickerson, Jonathan W; Watson, Katherine J; Kapolka, Nicholas J; Boutaud, Olivier; Rook, Jerri M; Blackwell, Timothy S; Roth, Bryan L; Harrison, Fiona E; Austin, Eric D; West, James D; Lindsley, Craig W; Merryman, W David.
Afiliação
  • Valentine MS; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
  • Bender AM; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Shay S; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Paffenroth KC; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
  • Gladson S; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Dickerson JW; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Watson KJ; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Kapolka NJ; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • Boutaud O; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Rook JM; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Blackwell TS; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Roth BL; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • Harrison FE; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Austin ED; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • West JD; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Lindsley CW; Warren Center for Neuroscience Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University, Nashville, Tennessee, USA.
  • Merryman WD; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
JACC Basic Transl Sci ; 8(10): 1379-1388, 2023 Oct.
Article em En | MEDLINE | ID: mdl-38094686
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article