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

AUTHORS

Valentine MSMichael S , Bender AMAaron M , Shay SSheila , Paffenroth KCKrista C , Gladson SSanthi , Dickerson JWJonathan W , Watson KJKatherine J , Kapolka NJNicholas J , Boutaud OOlivier , Rook JMJerri M , Blackwell TSTimothy S , Roth BLBryan L , Harrison FEFiona E , Austin EDEric D , West JDJames D , Lindsley CWCraig W , Merryman WDW David . JACC. Basic to translational science. 2023 09 13; 8(10). 1379-1388

PMID: 38094686[PubMed].

ABSTRACT

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