ALPIDEM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H23Cl2N3O
Molecular Weight	404.333
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCN(CCC)C(=O)CC1=C(N=C2C=CC(Cl)=CN12)C3=CC=C(Cl)C=C3

InChI

InChIKey=JRTIDHTUMYMPRU-UHFFFAOYSA-N

InChI=1S/C21H23Cl2N3O/c1-3-11-25(12-4-2)20(27)13-18-21(15-5-7-16(22)8-6-15)24-19-10-9-17(23)14-26(18)19/h5-10,14H,3-4,11-13H2,1-2H3

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22981367

Alpidem is an imidazopyridine anxiolytic acting as a partial agonist at γ-aminobutyric acid A (GABA(A)) receptor. Alpidem is selective for GABAA receptors bearing α1 subunits. Alpidem was briefly marketed for the treatment of anxiety, but was withdrawn because of liver toxicity.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GABA-A receptor; benzodiazepine site 38 Target ID: CHEMBL2109243 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22981367	Partial Agonist 290		1.67 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Anxiety 267 Sources: https://www.ncbi.nlm.nih.gov/pubmed/1974073	Primary		Withdrawn	ANANXYL Approved Use Alpidem was used in the treatment of various anxiety syndromes

PubMed

Title	Date	PubMed
Effects of single doses of alpidem, lorazepam, and placebo on memory and attention in healthy young and elderly volunteers.	1990 May	1974070
Repeated treatment with alpidem, a new anxiolytic, does not induce tolerance or physical dependence.	1993 Sep	7901790
[A new case of hepatitis after alpidem monotherapy].	1994	7875405
[Hepatitis induced by alpidem (Ananxyl). Four cases, one of them fatal].	1994	7750686
[Subfulminant hepatitis caused by alpidem and treated by liver transplantation].	1995 Feb	7750714
Eotaxin expression and eosinophil infiltrate in the liver of patients with drug-induced liver disease.	2001 Apr	11394653
A structure-activity relationship study of the affinity of selected imidazo[1,2-a]pyridine derivatives, congeners of zolpidem, for the omega 1-subtype of the benzodiazepine receptor.	2001 Jan-Feb	11370287
[3H]Ro 15-1788 binding sites to brain membrane of the saltwater Mugil cephalus.	2001 Mar	11255103
Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation.	2001 Nov	11602696
2-Arylpyrazolo[1,5-a]pyrimidin-3-yl acetamides. New potent and selective peripheral benzodiazepine receptor ligands.	2001 Oct	11557354
SSR180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), a peripheral benzodiazepine receptor ligand, promotes neuronal survival and repair.	2002 Jun	12023539
GABAA-benzodiazepine receptor complex ligands and stress-induced hyperthermia in singly housed mice.	2002 May	11900786
[Hepatic tolerance of atypical antipsychotic drugs].	2002 Nov-Dec	12506267
Alpidem analogues containing a GABA or glycine moiety as new anticonvulsant agents.	2003 Mar	12659934
Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands.	2004 Jan 15	14723961
Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124].	2004 Mar 4	15102335
Effects of calcium channel blockers on antidepressant action of Alprazolam and Imipramine.	2007 Dec 1	21503240
Synthesis and structure-activity relationship studies in peripheral benzodiazepine receptor ligands related to alpidem.	2008 Mar 15	18294852
Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins.	2009 Dec	19720731
Zolpidem, a clinical hypnotic that affects electronic transfer, alters synaptic activity through potential GABA receptors in the nervous system without significant free radical generation.	2009 Jan-Mar	20046645
6-Benzyl-3,4-dimeth-oxy-10-methyl-pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-one.	2009 Sep 12	21577919
General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: one-pot synthesis of alpidem and zolpidem.	2010 Apr 1	20213787
Ethyl 8-(4-nitro-phen-yl)imidazo[1,2-a]pyridine-7-carboxyl-ate.	2010 Nov 24	21589555
Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease.	2012 Oct	22700542
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.	2014 Jan	24085192

Patents

Sample Use Guides

In Vivo Use Guide

The anxiolytic dose range: 75–150 mg administered in two or three daily doses - i.e., single doses of 25–75 mg

Route of Administration: Oral

In Vitro Use Guide

At 250 to 500 microM, alpidem prevented calcium-induced mitochondrial permeability transition (MPT) in isolated mitochondria, but caused severe glutathione depletion in hepatocytes that was increased by 3-methylcholanthrene, a cytochrome P4501A inducer, and decreased by cystine, a glutathione precursor. Although cell calcium increased, mitochondrial cytochrome c did not translocate to the cytosol and cells died of necrosis. Cell death was prevented by cystine, but not cyclosporin A, an MPT inhibitor. At low concentrations (25-50 microM), in contrast, alpidem accelerated calcium-induced MPT in mitochondria. It did not deplete glutathione in hepatocytes, but nevertheless caused some cell death that was prevented by cyclosporin A, but not by cystine. Alpidem (10 microM) also increased the toxicity of tumor necrosis factor-alpha (1 ng/ml) in hepatocytes. In conclusion, low concentrations of alpidem increase both calcium-induced MPT in mitochondria, and TNF-alpha toxicity in cells, like other PBR ligands.

Name

Type

Language

ALPIDEM

Official Name

English

alpidem [INN]

Common Name

English

6-CHLORO-2-(P-CHLOROPHENYL)-N,N-DIPROPYLIMIDAZO(1,2-A)PYRIDINE-3-ACETAMIDE

Common Name

English

ALPIDEM [MI]

Common Name

English

Alpidem [WHO-DD]

Common Name

English

ALPIDEM [USAN]

Common Name

English

SL 80.0342-00

Code

English

IMIDAZO(1,2-A)PYRIDINE-3-ACETAMIDE, 6-CHLORO-2-(4-CHLOROPHENYL)-N,N-DIPROPYL-

Systematic Name

English

SL-80.0342-00

Code

English

ALPIDEM [MART.]

Common Name

English

6-Chloro-2-(4-chlorophenyl)-N,N-dipropylimidazo[1,2-a]pyridine-3-acetamide

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C29756