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Identification
NameLesopitron
Accession NumberDB04970
TypeSmall Molecule
GroupsInvestigational
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 Identifiers
  • E-4424
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
UNIIH1CGM4755H
CAS number132449-46-8
WeightAverage: 320.82
Monoisotopic: 320.151622409
Chemical FormulaC15H21ClN6
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazinanes
Sub ClassPiperazines
Direct ParentN-arylpiperazines
Alternative Parents
Substituents
  • N-arylpiperazine
  • Dialkylarylamine
  • N-alkylpiperazine
  • Pyrimidine
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • Pyrazole
  • Azole
  • Tertiary aliphatic amine
  • Tertiary amine
  • Azacycle
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationIntended for the treatment of anxiety disorders.
PharmacodynamicsIn 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 actionLesopitron 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.
Related Articles
AbsorptionRapidly 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 distributionNot Available
Protein bindingNot Available
Metabolism

Hepatic, the main metabolite being 5-hydroxylesopitron.

Route of eliminationNot Available
Half life1.1 to 5.6 hours
ClearanceNot Available
ToxicityThe 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot 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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
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
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot 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 signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G pro...
Gene Name:
HTR1A
Uniprot ID:
P08908
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 ]
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Drug created on October 21, 2007 16:23 / Updated on September 16, 2013 17:26