Identification

Name
Cariprazine
Accession Number
DB06016
Type
Small Molecule
Groups
Approved, Investigational
Description

Cariprazine is an antipsychotic drug developed by Gedeon Richter and marketed by Actavis under the trade name Vraylar. Cariprazine acts as a D2 and D3 receptor partial agonist, with high selectivity towards the D3 receptor. This mechanism is relatively unique, since many other antipsychotics are D2 and 5-HT2A agonists. Cariprazine was approved by the FDA in September 2015 and is indicated in the treatment of schizophrenia and bipolar disorder. Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder.

Structure
Thumb
Synonyms
  • Cariprazine
  • trans-N-{4-[2-[4-(2,3-dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl}-N’,N’-dimethylurea hydrochloride
External IDs
MP-214 / RGH-188
Product Ingredients
IngredientUNIICASInChI Key
Cariprazine hydrochlorideKQD7C255YG1083076-69-0GPPJWWMREQHLQT-BHQIMSFRSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VraylarCapsule, gelatin coated1.5 mg/1OralAllergan, Inc.2015-09-17Not applicableUs
VraylarCapsule, gelatin coated4.5 mg/1OralAllergan, Inc.2015-09-17Not applicableUs
VraylarCapsule, gelatin coated3 mg/1OralAllergan, Inc.2015-09-17Not applicableUs
VraylarCapsule, gelatin coated6 mg/1OralAllergan, Inc.2015-09-17Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
VraylarCariprazine (1.5 mg/1) + Cariprazine (3 mg/1)KitOralAllergan, Inc.2015-09-17Not applicableUs
VraylarCariprazine (1.5 mg/1) + Cariprazine (3 mg/1)KitOralAllergan, Inc.2015-09-17Not applicableUs
Categories
UNII
F6RJL8B278
CAS number
839712-12-8
Weight
Average: 427.41
Monoisotopic: 426.1953171
Chemical Formula
C21H32Cl2N4O
InChI Key
KPWSJANDNDDRMB-QAQDUYKDSA-N
InChI
InChI=1S/C21H32Cl2N4O/c1-25(2)21(28)24-17-8-6-16(7-9-17)10-11-26-12-14-27(15-13-26)19-5-3-4-18(22)20(19)23/h3-5,16-17H,6-15H2,1-2H3,(H,24,28)/t16-,17-
IUPAC Name
3,3-dimethyl-1-[(1r,4r)-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl]urea
SMILES
CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(CC2)C2=C(Cl)C(Cl)=CC=C2)CC1

Pharmacology

Indication

Cariprazine is an atypical antipsychotic indicated for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder.

Associated Conditions
Pharmacodynamics

Cariprazine acts as a partial agonist at the dopamine D3 and D2 receptors with high binding affinity. Cariprazine acts as an antagonist at 5-HT2B and 5-HT2A receptors with high and moderate binding affinity as well as it binds to the histamine H1 receptors. Cariprazine shows lower binding affinity to the serotonin 5­ HT2C and α1A- adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors.

Mechanism of action

The mechanism of action of cariprazine in schizophrenia and bipolar I disorder is unknown. However, the efficacy of cariprazine could be mediated through a combination of partial agonist activity at central dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Cariprazine forms two major metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), that have in vitro receptor binding profiles similar to the parent drug.

TargetActionsOrganism
AD(3) dopamine receptor
agonist
partial agonist
Human
AD(2) dopamine receptor
agonist
partial agonist
Human
A5-hydroxytryptamine receptor 1A
agonist
partial agonist
Human
A5-hydroxytryptamine receptor 2B
antagonist
Human
A5-hydroxytryptamine receptor 2A
antagonist
Human
AHistamine H1 receptor
antagonist
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

Cariprazine and its metabolites are highly protein bound (91-97%).

Metabolism

Cariprazine is extensively metabolized by hydroxylation and demethylation. It is primarily metabolized by CYP3A4, and CYP2D6 to a lesser extent to active metabolites desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). DCAR is then further metabolized to DDCAR by CYP3A4 and CYP2D6, and DDCAR is then metabolized by CYP3A4 to a hydroxylated metabolite. Both DCAR and DDCAR display similar functions and are as pharmacologically potent as the parent drug.

Route of elimination

Urine (21% of dose)

Half life

~1 week for the combined drug.

Clearance
Not Available
Toxicity

Accidental acute overdosage (48 mg/day) was reported in one patient. This patient experienced orthostasis and sedation. The patient fully recovered the same day. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Cariprazine is not approved for the treatment of patients with dementia-related psychosis.

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 Cariprazine is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of adverse effects can be increased when Cariprazine is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Cariprazine.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Cariprazine.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Cariprazine.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of serotonin syndrome can be increased when Cariprazine 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 Cariprazine.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Cariprazine.
3,5-DinitrocatecholThe therapeutic efficacy of 3,5-Dinitrocatechol can be decreased when used in combination with Cariprazine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of serotonin syndrome can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Cariprazine.
Food Interactions
No interactions found.

References

Synthesis Reference

Agai-Csongor E, Domany G, Nogradi K, Galambos J, Vago I, Keseru GM, Greiner I, Laszlovszky I, Gere A, Schmidt E, Kiss B, Vastag M, Tihanyi K, Saghy K, Laszy J, Gyertyan I, Zajer-Balazs M, Gemesi L, Kapas M, Szombathelyi Z: Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors. Bioorg Med Chem Lett. 2012 May 15;22(10):3437-40. doi: 10.1016/j.bmcl.2012.03.104. Epub 2012 Apr 4. Pubmed

General References
  1. Citrome L: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206. doi: 10.1517/17425255.2013.759211. [PubMed:23320989]
  2. McCormack PL: Cariprazine: First Global Approval. Drugs. 2015 Nov;75(17):2035-43. doi: 10.1007/s40265-015-0494-7. [PubMed:26510944]
External Links
KEGG Drug
D09997
PubChem Compound
11154555
PubChem Substance
310264859
ChemSpider
25999972
BindingDB
50443101
ChEBI
90933
ChEMBL
CHEMBL2028019
Drugs.com
Drugs.com Drug Page
Wikipedia
Cariprazine
ATC Codes
N05AX15 — Cariprazine
FDA label
Download (525 KB)
MSDS
Download (61.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentPharmacokinetic Profile1
1CompletedTreatmentSchizophrenic Disorders1
2CompletedTreatmentBipolar Disorder (BD)1
2CompletedTreatmentDepression, Bipolar2
2CompletedTreatmentMajor Depressive Disorder (MDD)2
2CompletedTreatmentSchizophrenic Disorders4
2RecruitingTreatmentCocaine Use Disorders1
2, 3CompletedTreatmentSchizophrenic Disorders5
3CompletedPreventionSchizophrenic Disorders1
3CompletedTreatmentBipolar Disorder (BD) / Depression2
3CompletedTreatmentBipolar Disorder (BD) / Mania1
3CompletedTreatmentBipolar I Disorder1
3CompletedTreatmentBipolar I Disorder / Mania1
3CompletedTreatmentMajor Depressive Disorder (MDD)2
3CompletedTreatmentSchizophrenic Disorders3
3Not Yet RecruitingTreatmentMajor Depressive Disorder (MDD)2
3RecruitingTreatmentBipolar I Disorder / Depression / Mania1
3RecruitingTreatmentSchizophrenic Disorders1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Capsule, gelatin coatedOral1.5 mg/1
Capsule, gelatin coatedOral3 mg/1
Capsule, gelatin coatedOral4.5 mg/1
Capsule, gelatin coatedOral6 mg/1
KitOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7737142No2010-06-152027-03-27Us
US7943621No2011-05-172028-12-16Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0279 mg/mLALOGPS
logP4.56ALOGPS
logP4.06ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)15.68ChemAxon
pKa (Strongest Basic)7.91ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area38.82 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity117.81 m3·mol-1ChemAxon
Polarizability48.07 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Dichlorobenzenes / Dialkylarylamines / Aniline and substituted anilines / N-alkylpiperazines / Aryl chlorides / Ureas / Trialkylamines / Azacyclic compounds / Organopnictogen compounds
show 4 more
Substituents
Phenylpiperazine / N-arylpiperazine / 1,2-dichlorobenzene / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aniline or substituted anilines / N-alkylpiperazine / Chlorobenzene / Halobenzene / Aryl halide
show 20 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Partial agonist
General Function
G-protein coupled amine receptor activity
Specific Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation.
Gene Name
DRD3
Uniprot ID
P35462
Uniprot Name
D(3) dopamine receptor
Molecular Weight
44224.335 Da
References
  1. Citrome L: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206. doi: 10.1517/17425255.2013.759211. [PubMed:23320989]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Partial agonist
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
References
  1. Citrome L: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206. doi: 10.1517/17425255.2013.759211. [PubMed:23320989]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Partial agonist
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. McCormack PL: Cariprazine: First Global Approval. Drugs. 2015 Nov;75(17):2035-43. doi: 10.1007/s40265-015-0494-7. [PubMed:26510944]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation...
Gene Name
HTR2B
Uniprot ID
P41595
Uniprot Name
5-hydroxytryptamine receptor 2B
Molecular Weight
54297.41 Da
References
  1. McCormack PL: Cariprazine: First Global Approval. Drugs. 2015 Nov;75(17):2035-43. doi: 10.1007/s40265-015-0494-7. [PubMed:26510944]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
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. McCormack PL: Cariprazine: First Global Approval. Drugs. 2015 Nov;75(17):2035-43. doi: 10.1007/s40265-015-0494-7. [PubMed:26510944]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
References
  1. McCormack PL: Cariprazine: First Global Approval. Drugs. 2015 Nov;75(17):2035-43. doi: 10.1007/s40265-015-0494-7. [PubMed:26510944]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Citrome L: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206. doi: 10.1517/17425255.2013.759211. [PubMed:23320989]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Citrome L: Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013 Feb;9(2):193-206. doi: 10.1517/17425255.2013.759211. [PubMed:23320989]

Drug created on November 18, 2007 11:29 / Updated on December 16, 2018 06:51