Identification

Name
Pimavanserin
Accession Number
DB05316
Type
Small Molecule
Groups
Approved, Investigational
Description

Pimavanserin (ACP-103), marketed under the trade name Nuplazid, is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors. As of September 3, 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson's disease psychosis, and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication. It is expected to improve the effectiveness and side effect profile of antipsychotics. The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012 and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses of risperidone and improve the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms. On September 2, 2014, the United States Food and Drug administration granted Breakthrough Therapy status to Acadia's New Drug Application for pimavanserin.

Structure
Thumb
Synonyms
Not Available
External IDs
ACP 103 / ACP-103 / ACP103
Product Ingredients
IngredientUNIICASInChI Key
Pimavanserin tartrateNA83F1SJSR706782-28-7RGSULKHNAKTFIZ-CEAXSRTFSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NuplazidCapsule34 mg/1OralACADIA Pharmaceuticals Inc2018-06-28Not applicableUs
NuplazidTablet, coated10 mg/1OralACADIA Pharmaceuticals Inc2018-06-28Not applicableUs
NuplazidTablet, coated17 mg/1OralACADIA Pharmaceuticals Inc2016-04-29Not applicableUs
Categories
UNII
JZ963P0DIK
CAS number
706779-91-1
Weight
Average: 427.564
Monoisotopic: 427.26350551
Chemical Formula
C25H34FN3O2
InChI Key
RKEWSXXUOLRFBX-UHFFFAOYSA-N
InChI
InChI=1S/C25H34FN3O2/c1-19(2)18-31-24-10-6-20(7-11-24)16-27-25(30)29(23-12-14-28(3)15-13-23)17-21-4-8-22(26)9-5-21/h4-11,19,23H,12-18H2,1-3H3,(H,27,30)
IUPAC Name
1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-{[4-(2-methylpropoxy)phenyl]methyl}urea
SMILES
CC(C)COC1=CC=C(CNC(=O)N(CC2=CC=C(F)C=C2)C2CCN(C)CC2)C=C1

Pharmacology

Indication

Investigated for use/treatment in neurologic disorders, parkinson's disease, psychosis, schizophrenia and schizoaffective disorders, and sleep disorders.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

ACP-103 reduces haloperidol-induced akathisia, a debilitating extrapyramidal side effect (EPS), in patients with schizophrenia. ACP-103 is a 5-HT2A inverse agonist, to reduce the side effects associated with antipsychotic drug treatment with haloperidol. ACP-103 reduced both the motor disturbances and hyperprolactinemia, a condition of elevated prolactin secretion, caused by haloperidol treatment.

TargetActionsOrganism
A5-hydroxytryptamine receptor 2A
inverse agonist
Human
UD(2) dopamine receptorNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of adverse effects can be increased when Pimavanserin is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Pimavanserin is combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Pimavanserin.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Pimavanserin is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of serotonin syndrome can be increased when 3,4-Methylenedioxyamphetamine is combined with Pimavanserin.
3,5-DinitrocatecholThe therapeutic efficacy of 3,5-Dinitrocatechol can be decreased when used in combination with Pimavanserin.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Pimavanserin.
4-hydroxycoumarinThe risk or severity of adverse effects can be increased when Pimavanserin is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Pimavanserin.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of serotonin syndrome can be increased when Pimavanserin is combined with 5-methoxy-N,N-dimethyltryptamine.
Food Interactions
Not Available

References

General References
  1. Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, Vanover KE, Hacksell U, Brann MR, Davis RE, Weiner DM: PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008 Mar;11(2):163-71. Epub 2007 Aug 21. [PubMed:17708779]
External Links
PubChem Compound
10071196
PubChem Substance
175426976
ChemSpider
8246736
BindingDB
139370
ChEBI
133017
ChEMBL
CHEMBL2111101
Wikipedia
Pimavanserin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentAdjunctive Treatment of Major Depressive Disorder1
2Active Not RecruitingTreatmentAgitation and Aggression in Alzheimer's Disease1
2CompletedTreatmentAgitation and Aggression in Alzheimer's Disease1
2CompletedTreatmentAlzheimer's Disease Psychosis1
2CompletedTreatmentDyskinesias / Parkinson's Disease (PD)1
2CompletedTreatmentHallucinations / Parkinson's Disease (PD) / Psychosis1
2CompletedTreatmentParkinson's Disease Psychosis1
2CompletedTreatmentSchizophrenic Disorders1
2RecruitingTreatmentAdjunctive Treatment of Depression Associated With Parkinson's Disease (PD) / Treatment of Depression in Adults With Parkinson's Disease (PD)1
2RecruitingTreatmentSchizophrenic Disorders1
3CompletedTreatmentParkinson's Disease Psychosis4
3RecruitingTreatmentDementia-related Psychosis1
3RecruitingTreatmentNeuropsychiatric Symptoms Related to Neurodegenerative Disease2
3RecruitingTreatmentSchizophrenic Disorders2
Not AvailableApproved for MarketingNot AvailableParkinson's Disease Psychosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral34 mg/1
Tablet, coatedOral10 mg/1
Tablet, coatedOral17 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9296694No2001-03-062021-03-06Us
US8110574No2000-12-132020-12-13Us
US7601740No2007-06-172027-06-17Us
US7732615No2008-06-032028-06-03Us
US7923564No2005-09-262025-09-26Us
US6756393No2001-03-062021-03-06Us
US7858789No2000-12-132020-12-13Us
US7115634No2001-10-062021-10-06Us
US7659285No2006-08-242026-08-24Us
US6815458No2001-03-062021-03-06Us
US8618130No2004-01-152024-01-15Us
US8921393No2004-01-152024-01-15Us
US9566271No2004-01-152024-01-15Us
US9765053No2002-07-272022-07-27Us
US10028944No2004-01-152024-01-15Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00748 mg/mLALOGPS
logP4.19ALOGPS
logP4.01ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)15.06ChemAxon
pKa (Strongest Basic)8.44ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area44.81 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity122.93 m3·mol-1ChemAxon
Polarizability47.76 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.696
Blood Brain Barrier-0.8018
Caco-2 permeable-0.6395
P-glycoprotein substrateSubstrate0.8782
P-glycoprotein inhibitor INon-inhibitor0.685
P-glycoprotein inhibitor IINon-inhibitor0.8743
Renal organic cation transporterNon-inhibitor0.799
CYP450 2C9 substrateNon-substrate0.7844
CYP450 2D6 substrateNon-substrate0.8342
CYP450 3A4 substrateSubstrate0.5769
CYP450 1A2 substrateNon-inhibitor0.8285
CYP450 2C9 inhibitorNon-inhibitor0.7474
CYP450 2D6 inhibitorNon-inhibitor0.8458
CYP450 2C19 inhibitorNon-inhibitor0.8247
CYP450 3A4 inhibitorNon-inhibitor0.9552
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8855
Ames testNon AMES toxic0.6638
CarcinogenicityNon-carcinogens0.8967
BiodegradationNot ready biodegradable0.9775
Rat acute toxicity2.4414 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8668
hERG inhibition (predictor II)Inhibitor0.7703
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 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 phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol ethers
Sub Class
Not Available
Direct Parent
Phenol ethers
Alternative Parents
Phenoxy compounds / Fluorobenzenes / Alkyl aryl ethers / Piperidines / Aryl fluorides / Ureas / Trialkylamines / Azacyclic compounds / Organopnictogen compounds / Organofluorides
show 3 more
Substituents
Phenoxy compound / Phenol ether / Alkyl aryl ether / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Piperidine / Carbonic acid derivative
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inverse agonist
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Friedman JH: Pimavanserin for the treatment of Parkinson's disease psychosis. Expert Opin Pharmacother. 2013 Oct;14(14):1969-75. doi: 10.1517/14656566.2013.819345. [PubMed:24016069]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Potassium channel regulator activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da

Drug created on November 18, 2007 11:23 / Updated on November 02, 2018 08:49