VU0530244

{{Short description|Peripherally selective 5-HT2B antagonist}}

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| class = Selective peripherally restricted serotonin 5-HT_2B receptor antagonist

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| CAS_number = 1396886-30-8

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| PubChem = 71783796

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| ChemSpiderID = 30683125

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| synonyms = VU-0530244

| IUPAC_name = [5-(4-fluorophenyl)-2-methylpyrazol-3-yl]-[3-(6-methyl-1H-benzimidazol-2-yl)azetidin-1-yl]methanone

| C=22 | H=20 | F=1 | N=5 | O=1

| SMILES = CC1=CC2=C(C=C1)N=C(N2)C3CN(C3)C(=O)C4=CC(=NN4C)C5=CC=C(C=C5)F

| StdInChI = 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)

| StdInChIKey = JWLJKHOGMOIRDR-UHFFFAOYSA-N

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VU0530244 is a potent, selective, and putatively peripherally restricted serotonin 5-HT_2B receptor antagonist which was first described in 2023.{{cite journal | vauthors = ((Rosalind Franklin Society)) | title = Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for ASSAY and Drug Development Technologies | journal = ASSAY and Drug Development Technologies | volume = 22 | issue = 6 | pages = 277 | date = 1 September 2024 | pmid = 39250303 | doi = 10.1089/adt.2024.87345.rfs2023 }}{{cite web | last=Shapiro | first=Marissa | title=Emily Days wins Rosalind Franklin Society Special Award in Science for contributions to the journal ASSAY and Drug Development Technologies | website=Vanderbilt University | date=28 August 2024 | url=https://medschool.vanderbilt.edu/basic-sciences/2024/08/28/emily-days-wins-rosalind-franklin-society-special-award-in-science-for-contributions-to-the-journal-assay-and-drug-development-technologies/ | access-date=10 November 2024}}{{cite journal | vauthors = Bender AM, Valentine MS, Bauer JA, Days E, Lindsley CW, Merryman WD | title = Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen | journal = Assay and Drug Development Technologies | volume = 21 | issue = 3 | pages = 89–96 | date = April 2023 | pmid = 36930852 | pmc = 10122230 | doi = 10.1089/adt.2022.116 }} Another similar drug, VU0631019, was also described alongside VU0530244. They were identified via high-throughput screening (HTS).

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

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.{{cite journal | vauthors = Padhariya K, Bhandare R, Canney D, Velingkar V | title = Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists | journal = Cardiovascular & Hematological Disorders Drug Targets | volume = 17 | issue = 2 | pages = 86–104 | date = 2017 | pmid = 28676029 | doi = 10.2174/1871529X17666170703115111 }}{{cite journal | vauthors = Ayme-Dietrich E, Lawson R, Da-Silva S, Mazzucotelli JP, Monassier L | title = Serotonin contribution to cardiac valve degeneration: new insights for novel therapies? | journal = Pharmacological Research | volume = 140 | issue = | pages = 33–42 | date = February 2019 | pmid = 30208338 | doi = 10.1016/j.phrs.2018.09.009 }}{{cite journal | vauthors = Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD | title = 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery | journal = Journal of Medicinal Chemistry | volume = 66 | issue = 16 | pages = 11027–11039 | date = August 2023 | pmid = 37584406 | pmc = 11073569 | doi = 10.1021/acs.jmedchem.3c01178 }} 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.{{cite journal | vauthors = Devroye C, Cathala A, Piazza PV, Spampinato U | title = The central serotonin_2B receptor as a new pharmacological target for the treatment of dopamine-related neuropsychiatric disorders: Rationale and current status of research | journal = Pharmacology & Therapeutics | volume = 181 | issue = | pages = 143–155 | date = January 2018 | pmid = 28757154 | doi = 10.1016/j.pharmthera.2017.07.014 }} Such potential side effects can be avoided with the use of peripherally restricted serotonin 5-HT_2B receptor antagonists.

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.{{cite journal | vauthors = Rothman RB, Baumann MH | title = Serotonergic drugs and valvular heart disease | journal = Expert Opinion on Drug Safety | volume = 8 | issue = 3 | pages = 317–329 | date = May 2009 | pmid = 19505264 | pmc = 2695569 | doi = 10.1517/14740330902931524 }}{{cite journal | vauthors = Elangbam CS | title = Drug-induced valvulopathy: an update | journal = Toxicologic Pathology | volume = 38 | issue = 6 | pages = 837–848 | date = October 2010 | pmid = 20716786 | doi = 10.1177/0192623310378027 }}{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}{{cite journal | vauthors = Hutcheson JD, Setola V, Roth BL, Merryman WD | title = Serotonin receptors and heart valve disease--it was meant 2B | journal = Pharmacology & Therapeutics | volume = 132 | issue = 2 | pages = 146–157 | date = November 2011 | pmid = 21440001 | pmc = 3179857 | doi = 10.1016/j.pharmthera.2011.03.008 }}{{cite journal | vauthors = Seferian A, Chaumais MC, Savale L, Günther S, Tubert-Bitter P, Humbert M, Montani D | title = Drugs induced pulmonary arterial hypertension | journal = Presse Médicale | volume = 42 | issue = 9 Pt 2 | pages = e303–e310 | date = September 2013 | pmid = 23972547 | doi = 10.1016/j.lpm.2013.07.005 }} 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.{{cite journal | vauthors = McIntyre RS | title = Serotonin 5-HT_2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents | journal = Expert Opinion on Drug Safety | volume = 22 | issue = 10 | pages = 881–883 | date = 2023 | pmid = 37581427 | doi = 10.1080/14740338.2023.2248883 }}{{cite journal | vauthors = Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R | title = The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | journal = Journal of Psychopharmacology | volume = 37 | issue = 9 | pages = 876–890 | date = September 2023 | pmid = 37572027 | doi = 10.1177/02698811231190865 }}{{cite journal | vauthors = Rouaud A, Calder AE, Hasler G | title = Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins | journal = Journal of Psychopharmacology | volume = 38 | issue = 3 | pages = 217–224 | date = March 2024 | pmid = 38214279 | pmc = 10944580 | doi = 10.1177/02698811231225609 }}{{cite journal | vauthors = Wsół A | title = Cardiovascular safety of psychedelic medicine: current status and future directions | journal = Pharmacological Reports | volume = 75 | issue = 6 | pages = 1362–1380 | date = December 2023 | pmid = 37874530 | pmc = 10661823 | doi = 10.1007/s43440-023-00539-4 }} Selective serotonin 5-HT_2B receptor antagonism has been found to fully prevent the cardiotoxicity of dexnorfenfluramine in rodents.{{cite journal | vauthors = Dini G, Di Cara G, Ferrara P, Striano P, Verrotti A | title = Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding | journal = Neuropsychiatric Disease and Treatment | volume = 19 | issue = | pages = 2013–2025 | date = 2023 | pmid = 37790801 | pmc = 10543412 | doi = 10.2147/NDT.S417676 | doi-access = free }}{{cite journal | vauthors = Ayme-Dietrich E, Lawson R, Côté F, de Tapia C, Da Silva S, Ebel C, Hechler B, Gachet C, Guyonnet J, Rouillard H, Stoltz J, Quentin E, Banas S, Daubeuf F, Frossard N, Gasser B, Mazzucotelli JP, Hermine O, Maroteaux L, Monassier L | title = The role of 5-HT_2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors | journal = British Journal of Pharmacology | volume = 174 | issue = 22 | pages = 4123–4139 | date = November 2017 | pmid = 28806488 | pmc = 5680644 | doi = 10.1111/bph.13981 }}

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.