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ABT-354

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ABT-354
Clinical data
Other namesSLV-354, SLV354
Legal status
Legal status
  • Investigational
Identifiers
  • N-[[5-[[N-Ethyl-C-(4-ethyl-3,4-dihydropyrazol-2-yl)carbonimidoyl]sulfamoyl]thiophen-2-yl]methyl]benzamide
PubChem CID
Chemical and physical data
FormulaC20H25N5O3S2
Molar mass447.57 g·mol−1
3D model (JSmol)
  • CCC1CN(N=C1)C(=NCC)NS(=O)(=O)C2=CC=C(S2)CNC(=O)C3=CC=CC=C3
  • InChI=1S/C20H25N5O3S2/c1-3-15-12-23-25(14-15)20(21-4-2)24-30(27,28)18-11-10-17(29-18)13-22-19(26)16-8-6-5-7-9-16/h5-12,15H,3-4,13-14H2,1-2H3,(H,21,24)(H,22,26)
  • Key:MGPUNPTXLIXELQ-UHFFFAOYSA-N

ABT-354 (also known as SLV-354 or SLV354) is an investigational small molecule drug developed by AbbVie, Inc. as a selective antagonist of the serotonin 5-HT6 receptor (HTR6), with intended applications in the treatment of cognitive disorders such as mild-to-moderate Alzheimer’s disease.[1]

Mechanism of action

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ABT-354 selectively antagonizes the 5-HT6 receptor, a G protein-coupled receptor almost exclusively expressed in the central nervous system (CNS), where it modulates neurotransmitter systems including acetylcholine, glutamate, dopamine, and norepinephrine.[2] Blockade of 5-HT6 receptors has been shown in preclinical models to enhance cholinergic and glutamatergic neurotransmission, leading to improvements in cognitive performance and memory.[2][3] Evidence from animal studies indicates that both 5-HT6 receptor antagonists and agonists can paradoxically exert procognitive, antidepressant, and anxiolytic effects, demonstrates the complex pharmacology of this receptor class.[2][3]

Other 5-HT6 antagonists

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Despite promising preclinical results, several selective 5-HT6 receptor antagonists (e.g., idalopirdine, intepirdine) have failed to demonstrate significant cognitive benefits in late-stage clinical trials for Alzheimer’s disease, possibly due to the complexity of the disorder and the need for multitarget approaches.[3] Recent advances in drug design, such as the development of neutral antagonists and multitarget ligands, may offer new opportunities for therapeutic intervention.[4][5]

Clinical trials

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Clinical trials for ABT-354 have focused on assessing its safety, tolerability, and pharmacokinetics in patients with mild-to-moderate Alzheimer’s disease who are concurrently receiving stable doses of acetylcholinesterase inhibitors.[6] These studies included participants aged 55 to 90 years and employed multiple dosing regimens.[6]

References

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  1. ^ "Delving into the Latest Updates on SLV-354 with Synapse". synapse.patsnap.com. Retrieved 2025-05-29.
  2. ^ a b c Pyka P, Haberek W, Więcek M, Szymanska E, Ali W, Cios A, et al. (January 2024). "First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease". Journal of Medicinal Chemistry. 67 (2): 1580–1610. doi:10.1021/acs.jmedchem.3c02148. PMC 10823479. PMID 38190615.
  3. ^ a b c Nirogi R, Jayarajan P, Shinde A, Mohammed AR, Grandhi VR, Benade V, et al. (February 2023). "Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders". Biomolecules. 13 (2): 309. doi:10.3390/biom13020309. PMC 9953539. PMID 36830678.
  4. ^ Drop M, Koczurkiewicz-Adamczyk P, Bento O, Pietruś W, Satała G, Blicharz-Futera K, et al. (September 2024). "5-HT6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives". European Journal of Medicinal Chemistry. 275: 116615. doi:10.1016/j.ejmech.2024.116615. PMID 38936149.
  5. ^ van Loevezijn A, Venhorst J, Iwema Bakker WI, de Korte CG, de Looff W, Verhoog S, et al. (October 2011). "N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features". Journal of Medicinal Chemistry. 54 (20): 7030–7054. doi:10.1021/jm200466r. PMID 21866910.
  6. ^ a b "Study Details Page". www.abbvieclinicaltrials.com. Retrieved 2025-05-29.


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