Lesopitron

Identification

Name
Lesopitron
Accession Number
DB04970
Type
Small Molecule
Groups
Investigational
Description

Lesopitron is an anxiolytic with pre- and post-synaptic 5-HT1A agonist activity, which is under development by Esteve.

Structure
Thumb
Synonyms
  • Lesopitran
External IDs
E-4424
Categories
Not Available
UNII
H1CGM4755H
CAS number
132449-46-8
Weight
Average: 320.82
Monoisotopic: 320.151622409
Chemical Formula
C15H21ClN6
InChI Key
AHCPKWJUALHOPH-UHFFFAOYSA-N
InChI
InChI=1S/C15H21ClN6/c16-14-12-19-22(13-14)7-2-1-6-20-8-10-21(11-9-20)15-17-4-3-5-18-15/h3-5,12-13H,1-2,6-11H2
IUPAC Name
2-{4-[4-(4-chloro-1H-pyrazol-1-yl)butyl]piperazin-1-yl}pyrimidine
SMILES
ClC1=CN(CCCCN2CCN(CC2)C2=NC=CC=N2)N=C1

Pharmacology

Indication

Intended for the treatment of anxiety disorders.

Structured Indications
Not Available
Pharmacodynamics

In phase I trials in healthy volunteers, lesopitron was well tolerated in single doses up to 50 mg, and up to 45 mg/day in repeated doses. Lesopitron has negligible effects on alpha-adrenergic and dopaminergic receptors, and was more potent than structurally-related 5-HT1A agonists in rat social interaction and marmoset anxiety models. It also countered benzodiazepine withdrawal-induced anxiety in rodents. The acute toxicity of lesopitron is low and it does not potentiate the effects of alcohol or barbiturates. Long-term usage led to reductions in plasma glucose, triglycerides, phospholipids and cholesterol.

Mechanism of action

Lesopitron acts as a ligand for central serotonin 5-HT1A receptors. Lesopitron inhibits haloperidol-induced catalepsy that is the consequence of its action on 5-HT1A autoreceptors. The ability of lesopitron to induce 5-HT syndrome reflects post-synaptic 5-HT1A receptor activation and the reversion of 8-OHDPAT-induced 5-HT syndrome by lesopitron suggests a partial agonist effect on this receptor-type. Lesopitron induced a hypothermic effect due to the enhanced activation of post-synaptic 5-HT1A receptors. The agonist effect of lesopitron on 5-HT1A receptors and its marked hypothermic effect is an added value for this drug and a stimulus to the study of its possible neuroprotective action.

TargetActionsOrganism
U5-hydroxytryptamine receptor 1ANot AvailableHuman
Absorption

Rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour. The absolute bioavailability of lesopitron in rats was about 10%, suggesting an important first-pass effect.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Hepatic, the main metabolite being 5-hydroxylesopitron.

Route of elimination
Not Available
Half life

1.1 to 5.6 hours

Clearance
Not Available
Toxicity

The most commonly reported adverse events in all the panels in one study were headache, dizziness, and nausea [PMID: 8959472].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Fisas MA, Farre A, Camarasa J, Escubedo E: Effects of lesopitron on the central nervous system arising from its interaction with 5-HT1A receptors. Pharmacology. 2004 Oct;72(2):57-67. [PubMed:15331910]
  2. Sramek JJ, Fresquet A, Marion-Landais G, Hourani J, Jhee SS, Martinez L, Jensen CM, Bolles K, Carrington AT, Cutler NR: Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study. J Clin Psychopharmacol. 1996 Dec;16(6):454-8. [PubMed:8959472]
  3. Serafini MT, Puig S, Garcia-Encina G, Farran R, Garcia-Soret A, Moragon T, Martinez L: Absorption, distribution and excretion of [14C]-Lesopitron after single and repeated administration in rats and dogs. Methods Find Exp Clin Pharmacol. 1997 Jan-Feb;19(1):61-72. [PubMed:9098842]
  4. Micheli F: Lesopitron (Esteve). IDrugs. 2001 Feb;4(2):218-24. [PubMed:16032484]
External Links
PubChem Compound
60813
PubChem Substance
175426922
ChemSpider
54801
BindingDB
82365
ChEMBL
CHEMBL2105051

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.25 mg/mLALOGPS
logP2.64ALOGPS
logP2.09ChemAxon
logS-2.4ALOGPS
pKa (Strongest Basic)7.75ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area50.08 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity100.45 m3·mol-1ChemAxon
Polarizability34.97 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9388
Caco-2 permeable+0.5377
P-glycoprotein substrateSubstrate0.5064
P-glycoprotein inhibitor INon-inhibitor0.5352
P-glycoprotein inhibitor IIInhibitor0.5325
Renal organic cation transporterInhibitor0.8173
CYP450 2C9 substrateNon-substrate0.8939
CYP450 2D6 substrateNon-substrate0.727
CYP450 3A4 substrateNon-substrate0.5
CYP450 1A2 substrateInhibitor0.9287
CYP450 2C9 inhibitorInhibitor0.5
CYP450 2D6 inhibitorNon-inhibitor0.6038
CYP450 2C19 inhibitorInhibitor0.8001
CYP450 3A4 inhibitorNon-inhibitor0.8805
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8893
Ames testNon AMES toxic0.665
CarcinogenicityNon-carcinogens0.8502
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.6276 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.8734
hERG inhibition (predictor II)Inhibitor0.6537
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as n-arylpiperazines. These are organic compounds containing a piperazine ring where the nitrogen ring atom carries an aryl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
N-arylpiperazines
Alternative Parents
Dialkylarylamines / N-alkylpiperazines / Aminopyrimidines and derivatives / Aryl chlorides / Pyrazoles / Heteroaromatic compounds / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organochlorides
show 1 more
Substituents
N-arylpiperazine / Dialkylarylamine / Aminopyrimidine / N-alkylpiperazine / Aryl chloride / Aryl halide / Pyrimidine / Pyrazole / Azole / Heteroaromatic compound
show 11 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. Fisas MA, Farre A, Camarasa J, Escubedo E: Effects of lesopitron on the central nervous system arising from its interaction with 5-HT1A receptors. Pharmacology. 2004 Oct;72(2):57-67. [PubMed:15331910]
  2. Micheli F: Lesopitron (Esteve). IDrugs. 2001 Feb;4(2):218-24. [PubMed:16032484]

Drug created on October 21, 2007 16:23 / Updated on December 01, 2017 15:34