Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen.
Aaron M BenderMichael S ValentineJoshua A BauerEmily DaysCraig W LindsleyW David MerrymanPublished in: Assay and drug development technologies (2023)
Antagonists of the serotonin receptor 2B (5-HT 2B ) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT 2B antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier. Two exemplary compounds, VU0530244 and VU0631019, were predicted to have very limited potential for brain penetration in human subjects, a critical profile for the development of 5-HT 2B antagonists devoid of centrally-mediated adverse effects.
Keyphrases
- high throughput
- pulmonary arterial hypertension
- pulmonary hypertension
- single cell
- pulmonary artery
- endothelial cells
- atrial fibrillation
- bioinformatics analysis
- small molecule
- anti inflammatory
- white matter
- big data
- coronary artery
- aortic valve
- induced pluripotent stem cells
- combination therapy
- brain injury
- blood brain barrier
- artificial intelligence
- cerebral ischemia
- functional connectivity