Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen

2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery

“…Additionally, we have recently disclosed results from a high-throughput screen (HTS) aimed at identifying additional chemical matter for the development of structurally orthogonal 5-HT 2B antagonists. 129 Our HTS campaign led to the immediate identification of potent and selective compounds (5-HT 2B IC 50 values in the low nanomolar range; <50% inhibition of 5-HT 2A/2C at 10 μM). Furthermore, selected compounds from the most potent reconfirmed hits were chosen for profiling in the P-gp assay, with exemplary compounds showing a low potential for brain exposure in human subjects.…”

“…Furthermore, selected compounds from the most potent reconfirmed hits were chosen for profiling in the P-gp assay, with exemplary compounds showing a low potential for brain exposure in human subjects. 129 ■ CONCLUSIONS AND PERSPECTIVES While 5-HT 2B has historically been viewed as an antitarget by medicinal chemists, the assessment of a compound's mode of pharmacology at the receptor is crucial. The difference between 5-HT 2B agonism and antagonism could mean the difference between a cardiotoxic agent (fen-phen) and a disease-modifying treatment for PAH, VHD, and related disorders.…”

“…Further preclinical characterization with respect to functional pharmacology (and assessment for efficacy in similar rodent models) will be needed for this next-generation SB-204741-derived scaffold, and such studies are ongoing in our laboratories. Additionally, we have recently disclosed results from a high-throughput screen (HTS) aimed at identifying additional chemical matter for the development of structurally orthogonal 5-HT 2B antagonists . Our HTS campaign led to the immediate identification of potent and selective compounds (5-HT 2B IC 50 values in the low nanomolar range; <50% inhibition of 5-HT 2A/2C at 10 μM).…”

“…Our HTS campaign led to the immediate identification of potent and selective compounds (5-HT 2B IC 50 values in the low nanomolar range; <50% inhibition of 5-HT 2A/2C at 10 μM). Furthermore, selected compounds from the most potent reconfirmed hits were chosen for profiling in the P-gp assay, with exemplary compounds showing a low potential for brain exposure in human subjects …”

Dual N6/C7-Substituted 7-Deazapurine and Tricyclic Ribonucleosides with Affinity for G Protein-Coupled Receptors

“…To prevent formation of MeOH adduct 16, we removed the TES group with tetra-n-butylammonium fluoride (TBAF). This resulted in a mixture of ethynyl analogues 21 as the major products and around 20−30% of the corresponding cyclized isomers (22). The remaining ethynyl analogues 21 could be fully converted into the cyclized isomers 22 by treating the crude mixture with catalytic amounts of AgOTf in refluxing DCE.…”