NAV

Lesopitron

Identification

Generic Name
Lesopitron
DrugBank Accession Number
DB04970
Background

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

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 320.82
Monoisotopic: 320.151622409
Chemical Formula
C15H21ClN6
Synonyms
  • 2-(4-(4-(4-Chloropyrazol-1-yl)butyl)-1-piperazinyl)pyrimidine
  • Lesopitron
External IDs
  • E-4424
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Pharmacology

Indication

Intended for the treatment of anxiety disorders.

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Contraindications & Blackbox Warnings
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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 AvailableHumans
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

Adverse Effects
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Toxicity

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

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Not Available
Chemical TaxonomyProvided by Classyfire
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
Amine / Aminopyrimidine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Dialkylarylamine / Heteroaromatic compound / Hydrocarbon derivative
show 11 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
H1CGM4755H
CAS number
132449-46-8
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

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. [Article]
  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. [Article]
  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. [Article]
  4. Micheli F: Lesopitron (Esteve). IDrugs. 2001 Feb;4(2):218-24. [Article]
PubChem Compound
60813
PubChem Substance
175426922
ChemSpider
54801
BindingDB
82365
ChEMBL
CHEMBL2105051
ZINC
ZINC000001547604
Wikipedia
Lesopitron

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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)7.74Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area50.08 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity100.45 m3·mol-1Chemaxon
Polarizability34.99 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-MSsplash10-03fr-2910000000-0ff79ee3f0ac3ab5b8c3
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0019000000-d0b7a7f836410238a1e9
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0039000000-a61f3d6f7dd57f64daed
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0191000000-365573f0f3a70d078217
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-2092000000-4d1691a71984dff7f82f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f96-0290000000-e1a7e753e6e0bb10afea
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f8c-6390000000-ae876eb28edda17800d7
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-173.53908
predicted
DeepCCS 1.0 (2019)
[M+H]+175.89708
predicted
DeepCCS 1.0 (2019)
[M+Na]+181.99025
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. 5-hydroxytryptamine receptor 1A
Kind
Protein
Organism
Humans
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. [Article]
  2. Micheli F: Lesopitron (Esteve). IDrugs. 2001 Feb;4(2):218-24. [Article]

Drug created at October 21, 2007 22:23 / Updated at February 21, 2021 18:51