Cariprazine

Identification

Name

Cariprazine

Accession Number

DB06016

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.

Type

Small Molecule

Groups

Approved, Investigational

Structure

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Cariprazine (DB06016)

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Weight

Average: 427.41
Monoisotopic: 426.1953171

Chemical Formula

C₂₁H₃₂Cl₂N₄O

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

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

• Mixed manic depressive episode
• Schizophrenia
• Acute Manic episode

Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
ADopamine D3 receptor	agonist partial agonist	Humans
ADopamine D2 receptor	agonist partial agonist	Humans
A5-hydroxytryptamine receptor 1A	agonist partial agonist	Humans
A5-hydroxytryptamine receptor 2B	antagonist	Humans
A5-hydroxytryptamine receptor 2A	antagonist	Humans
AHistamine H1 receptor	antagonist	Humans

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

Adverse Effects

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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

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Cariprazine can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Cariprazine can be increased when combined with Abatacept.
Abiraterone	The metabolism of Cariprazine can be decreased when combined with Abiraterone.
Acebutolol	The metabolism of Cariprazine can be decreased when combined with Acebutolol.
Aceclofenac	The risk or severity of hypertension can be increased when Cariprazine is combined with Aceclofenac.
Acemetacin	The risk or severity of hypertension can be increased when Cariprazine is combined with Acemetacin.
Acenocoumarol	The risk or severity of adverse effects can be increased when Cariprazine is combined with Acenocoumarol.
Acetaminophen	The metabolism of Cariprazine can be decreased when combined with Acetaminophen.
Acetazolamide	The risk or severity of adverse effects can be increased when Acetazolamide is combined with Cariprazine.
Acetophenazine	The risk or severity of adverse effects can be increased when Acetophenazine is combined with Cariprazine.

Additional Data Available

Extended Description
Extended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
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Severity
Severity
A severity rating for each drug interaction, from minor to major.
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Evidence Level
Evidence Level
A rating for the strength of the evidence supporting each drug interaction.
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Action
Action
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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Food Interactions

No interactions found.

Products

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Cariprazine hydrochloride	KQD7C255YG	1083076-69-0	GPPJWWMREQHLQT-BHQIMSFRSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
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Vraylar	Capsule, gelatin coated	4.5 mg/1	Oral	Allergan, Inc.	2015-09-17	Not applicable
Vraylar	Capsule, gelatin coated	3 mg/1	Oral	Allergan, Inc.	2015-09-17	Not applicable
Vraylar	Capsule, gelatin coated	6 mg/1	Oral	Allergan, Inc.	2015-09-17	Not applicable
Vraylar	Capsule, gelatin coated	1.5 mg/1	Oral	Allergan, Inc.	2015-09-17	Not applicable

Additional Data Available

Application Number
Application Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
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Product Code
Product Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
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Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Vraylar	Cariprazine (1.5 mg/1) + Cariprazine (3 mg/1)	Kit	Oral	Allergan, Inc.	2015-09-17	Not applicable
Vraylar	Cariprazine (1.5 mg/1) + Cariprazine (3 mg/1)	Kit	Oral	Allergan, Inc.	2015-09-17	Not applicable

Categories

ATC Codes

N05AX15 — Cariprazine

• N05AX — Other antipsychotics
• N05A — ANTIPSYCHOTICS
• N05 — PSYCHOLEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Agents that produce hypertension
• Antidepressive Agents
• Antipsychotic Agents
• Antipsychotic Agents (Second Generation [Atypical])
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Histamine Antagonists
• Histamine H1 Antagonists
• Nervous System
• Neurotoxic agents
• Psycholeptics
• Psychotropic Drugs
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Serotonin 5-HT1 Receptor Agonists
• Serotonin 5-HT2 Receptor Antagonists
• Serotonin 5-HT2A Receptor Antagonists
• Serotonin Agents
• Serotonin Receptor Agonists
• Serotonin Receptor Antagonists
• Tranquilizing Agents

Chemical TaxonomyProvided by Classyfire

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 / Organochlorides / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds

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Substituents

1,2-dichlorobenzene / Amine / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonic acid derivative / Carbonyl group / Chlorobenzene / Dialkylarylamine / Halobenzene / Hydrocarbon derivative / Monocyclic benzene moiety / N-alkylpiperazine / N-arylpiperazine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organochloride / Organohalogen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Phenylpiperazine / Tertiary aliphatic amine / Tertiary aliphatic/aromatic amine / Tertiary amine / Urea

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Molecular Framework

Aromatic heteromonocyclic compounds

External Descriptors

Not Available

Chemical Identifiers

UNII

F6RJL8B278

CAS number

839712-12-8

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[[email protected]]1CC[[email protected]](CCN2CCN(CC2)C2=C(Cl)C(Cl)=CC=C2)CC1

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

RxNav

1667655

ChEBI

90933

ChEMBL

CHEMBL2028019

ZINC

ZINC000100907004

Drugs.com

Drugs.com Drug Page

Wikipedia

Cariprazine

FDA label

Download (525 KB)

MSDS

Download (61.7 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Prevention	Schizophrenia	1
3	Completed	Treatment	Bipolar Disorder (BD) / Depression	2
3	Completed	Treatment	Bipolar Disorder (BD) / Mania	1
3	Completed	Treatment	Bipolar Type I Disorder	1
3	Completed	Treatment	Bipolar Type I Disorder / Mania	1
3	Completed	Treatment	Major Depressive Disorder (MDD)	2
3	Completed	Treatment	Schizophrenia	3
3	Not Yet Recruiting	Treatment	Bipolar Type I Disorder / Schizophrenia	1
3	Recruiting	Treatment	Bipolar Type I Disorder / Depression / Mania	1
3	Recruiting	Treatment	Major Depressive Disorder (MDD)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Capsule		1.5 mg
Capsule		3 mg
Capsule		4.5 mg
Capsule		6 mg
Capsule	Oral
Capsule, gelatin coated	Oral	1.5 mg/1
Capsule, gelatin coated	Oral	3 mg/1
Capsule, gelatin coated	Oral	4.5 mg/1
Capsule, gelatin coated	Oral	6 mg/1
Kit	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
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US7737142	No	2010-06-15	2027-03-27
US7943621	No	2011-05-17	2028-12-16
USRE47350	No	2019-04-16	2029-07-16

Additional Data Available

Filed On
Filed On
The date on which a patent was filed with the relevant government.
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Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0279 mg/mL	ALOGPS
logP	4.56	ALOGPS
logP	4.06	ChemAxon
logS	-4.2	ALOGPS
pKa (Strongest Acidic)	15.68	ChemAxon
pKa (Strongest Basic)	7.91	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	38.82 Å2	ChemAxon
Rotatable Bond Count	5	ChemAxon
Refractivity	117.81 m3·mol-1	ChemAxon
Polarizability	48.07 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

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Drug created on November 18, 2007 11:29 / Updated on June 12, 2020 11:41