VU0530244

VU0530244 is a potent, selective, and putatively peripherally restricted serotonin 5-HT_2B receptor antagonist which was first described in 2023.^[1][2][3] Another similar drug, VU0631019, was also described alongside VU0530244.^[3] They were identified via high-throughput screening (HTS).^[3]

VU0530244

Clinical data
Other names	VU-0530244
Drug class	Selective peripherally restricted serotonin 5-HT2B receptor antagonist
Identifiers
IUPAC name [5-(4-fluorophenyl)-2-methylpyrazol-3-yl]-[3-(6-methyl-1H-benzimidazol-2-yl)azetidin-1-yl]methanone
CAS Number	1396886-30-8
PubChem CID	71783796
ChemSpider	30683125
Chemical and physical data
Formula	C22H20FN5O
Molar mass	389.434 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=CC2=C(C=C1)N=C(N2)C3CN(C3)C(=O)C4=CC(=NN4C)C5=CC=C(C=C5)F
InChI InChI=1S/C22H20FN5O/c1-13-3-8-17-19(9-13)25-21(24-17)15-11-28(12-15)22(29)20-10-18(26-27(20)2)14-4-6-16(23)7-5-14/h3-10,15H,11-12H2,1-2H3,(H,24,25) Key:JWLJKHOGMOIRDR-UHFFFAOYSA-N

The affinity (IC₅₀Tooltip half-maximal inhibitory concentration) of VU0530244 for the serotonin 5-HT_2B receptor was found to be 17.3 nM.^[3] Its affinity (IC₅₀) values at the serotonin 5-HT_2A and 5-HT_2C receptors were greater than 10,000 nM (>578-fold less than for the serotonin 5-HT_2B receptor).^[3] The drug is predicted to be a robust P-glycoprotein substrate and hence is expected to have very limited blood–brain barrier permeability.^[3]

Serotonin 5-HT_2B receptor antagonists are of interest for potential use in medicine to treat pulmonary arterial hypertension, valvular heart disease, and related cardiopathies.^[4][5][6][3] However, reduced serotonin 5-HT_2B receptor signaling in the central nervous system has been linked to adverse effects such as impulsivity, suicidality, and sleep disturbances, among others.^[7][3] Such potential side effects can be avoided with the use of peripherally restricted serotonin 5-HT_2B receptor antagonists.^[3]

In addition, activation of serotonin 5-HT_2B receptors is thought to be responsible for development of cardiac fibrosis and valvulopathy as well as pulmonary hypertension with certain serotonergic agents, including direct serotonin 5-HT_2B receptor agonists like cabergoline, ergotamine, methysergide, and pergolide, serotonin releasing agents like chlorphentermine and aminorex, and dual serotonin 5-HT_2B receptor agonists and serotonin releasing agents like fenfluramine, dexfenfluramine, benfluorex, and MDMA.^{[8][9][10][11][12]} Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin as well as entactogens like MDMA are also potent serotonin 5-HT_2B receptor agonists, and there have been concerns about chronic administration of these and related agents in medical contexts due to possible development of cardiac and other complications.^{[13][14][15][16]} Selective serotonin 5-HT_2B receptor antagonism has been found to fully prevent the cardiotoxicity of dexnorfenfluramine in rodents.^[17][18]

In 2024, the paper that described the discovery of the VU0530244 won the 2023 Rosalind Franklin Society Special Award in Science for contributions to the journal Assay and Drug Development Technologies.^[1][2]

See also

• BW-501C67
• Xylamidine