Details
Stereochemistry | ACHIRAL |
Molecular Formula | C18H15BrF2N4O2 |
Molecular Weight | 437.238 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
COC1=CC=C(NC(=O)NC2=CC=C(F)C=C2F)C=C1C3=C(Br)C=NN3C
InChI
InChIKey=COSPVUFTLGQDQL-UHFFFAOYSA-N
InChI=1S/C18H15BrF2N4O2/c1-25-17(13(19)9-22-25)12-8-11(4-6-16(12)27-2)23-18(26)24-15-5-3-10(20)7-14(15)21/h3-9H,1-2H3,(H2,23,24,26)
Nelotanserin is a potent, selective 5-HT(2A) inverse agonist. Originally called ADP-125, the compound was developed by Arena Pharmaceuticals as a treatment for insomnia, but failed efficacy measures for this indication in Phase 2. In 2015, Axovant Sciences licensed this compound for development, renamed it nelotanserin, and began evaluating it in dementia with Lewy bodies (DLB). Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT(2A) receptor with at least 30- and 5000-fold selectivity compared with 5-HT(2C) and 5-HT(2B) receptors, respectively. Nelotanserin dosed orally prevented (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT(2A) agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. Nelotanserin has been used in trials studying the treatment of Lewy body dementia, visual hallucinations, dementia with Lewy bodies, and REM sleep behavior disorder.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL224 Sources: https://www.alzforum.org/therapeutics/nelotanserin |
1.7 nM [IC50] | ||
Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19841476 |
79.0 nM [IC50] | ||
Target ID: CHEMBL1833 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19841476 |
791.0 nM [IC50] |
PubMed
Title | Date | PubMed |
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Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia. | 2010 Jan |
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Discovery of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (nelotanserin) and related 5-hydroxytryptamine2A inverse agonists for the treatment of insomnia. | 2010 Mar 11 |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT02640729
Lewy Body Dementia: Nelotanserin 40mg then nelotanserin 80 mg; once daily, oral, 20-mg tablets
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19841476
Results from IP accumulation assays suggest that Nelotanserin is a potent 5-HT2A full inverse agonist (IC50=1.7 nM), a moderately potent 5-HT2C partial inverse agonist (IC50=79 nM) (maximal response was 62% of the response obtained for the reference inverse agonist clozapine), and a weak 5-HT2B inverse agonist (IC50=791 nM). Nelotanserin displays high affinity for recombinant human 5-HT2A receptors (Ki=0.35 nM), moderate affinity for human 5-HT2C receptors (Ki=100 nM), and low affinity for human 5-HT2B receptors (2000 nM) stably expressed in HEK293 cells. The results suggest that Nelotanserin has a 262-fold higher affinity for human 5-HT2A than 5-HT2C receptors and a 6610-fold higher affinity for human 5-HT2A than 5-HT2B receptors.
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C66885
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ACTIVE MOIETY