NELOTANSERIN

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

Structure Search

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)

HIDE SMILES / InChI

Molecular Formula	C18H15BrF2N4O2
Molecular Weight	437.238
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.alzforum.org/therapeutics/nelotanserin | https://www.ncbi.nlm.nih.gov/pubmed/19841476 | https://adisinsight.springer.com/drugs/800021795

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	Potency
Serotonin 2a (5-HT2a) receptor 231 Target ID: CHEMBL224 Sources: https://www.alzforum.org/therapeutics/nelotanserin	Inverse Agonist 80	1.7 nM [IC50]
Serotonin 2c (5-HT2c) receptor 124 Target ID: CHEMBL225 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19841476	Inverse Agonist 80	79.0 nM [IC50]
Serotonin 2b (5-HT2b) receptor 60 Target ID: CHEMBL1833 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19841476	Inverse Agonist 80	791.0 nM [IC50]

PubMed

Title	Date	PubMed
Nelotanserin, a novel selective human 5-hydroxytryptamine2A inverse agonist for the treatment of insomnia.	2010 Jan	19841476
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	20143782

Patents

Sample Use Guides

In Vivo Use Guide

Lewy Body Dementia: Nelotanserin 40mg then nelotanserin 80 mg; once daily, oral, 20-mg tablets

Route of Administration: Oral

In Vitro Use Guide

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.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 17:58:22 UTC 2023` Edited by `admin` on `Sat Dec 16 17:58:22 UTC 2023`
Record UNII	4ZA73QEW2P
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NELOTANSERIN

Official Name

English

APD125

Code

English

nelotanserin [INN]

Common Name

English

1-(3-(4-BROMO-2-METHYL-2H-PYRAZOL-3-YL)-4-METHOXYPHENYL)-3-(2,4- DIFLUOROPHENYL)UREA

Systematic Name

English

1-[3-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea

Systematic Name

English

UREA, N-(3-(4-BROMO-1-METHYL-1H-PYRAZOL-5-YL)-4-METHOXYPHENYL)-N'-(2,4-DIFLUOROPHENYL)-

Systematic Name

English

NELOTANSERIN [USAN]

Common Name

English

APD-125

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C66885