CLOZAPINE HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C18H19ClN4.ClH
Molecular Weight	363.284
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

Cl.CN1CCN(CC1)C2=NC3=CC(Cl)=CC=C3NC4=CC=CC=C24

InChI

InChIKey=ARWPDHKDEREYEE-UHFFFAOYSA-N

InChI=1S/C18H19ClN4.ClH/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18;/h2-7,12,20H,8-11H2,1H3;1H

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Description

Clozapine was discovered in 1958 by an anesthetist and now it is used for the treatment of schizophrenia. Although the exact mechanism of its action is unknown, the effect of clozapine on schizophrenia is associated with inhibition of dopamine D2 and serotonin 2A receptors.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dopamine D2 receptor 311	Antagonist 2,849		160.0 nM [Ki]
Serotonin 2a (5-HT2a) receptor 237	Antagonist 2,849		5.4 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Treatment-resistant schizophrenia 2	Primary		Approved 8,583	CLOZARIL

C_max

Value	Dose	Co-administered	Analyte	Population
319 ng/mL	100 mg 2 times / day steady-state, oral		CLOZAPINE plasma	Homo sapiens
98 nM	12.5 mg single, oral		CLOZAPINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1348 nM × h	12.5 mg single, oral		CLOZAPINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 h	100 mg 2 times / day steady-state, oral		CLOZAPINE plasma	Homo sapiens
18.6 h	12.5 mg single, oral		CLOZAPINE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
3%	100 mg 2 times / day steady-state, oral		CLOZAPINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
289 mg 1 times / day multiple, oral Recommended	unhealthy, 41	Other AEs: Sedation, Salivation...
296 mg 1 times / day multiple, oral Recommended	unhealthy, 74.2 years (range: 65-89 years)	Disc. AE: Orthostatic hypotension, Sedation... Other AEs: Sedation, Hypersalivation...
450 mg 1 times / day multiple, oral Recommended	unhealthy, adult	Other AEs: Dry mouth, Urinary hesitancy...
900 mg 1 times / day multiple, oral Recommended	unhealthy, adult	Other AEs: Drowsiness, Tachycardia...

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AEs

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AE	Significance	Dose	Population
Sedation	14 patients	289 mg 1 times / day multiple, oral Recommended	unhealthy, 41
Dizziness	4 patients	289 mg 1 times / day multiple, oral Recommended	unhealthy, 41
Fever	4 patients	289 mg 1 times / day multiple, oral Recommended	unhealthy, 41
Nausea and vomiting	5 patients	289 mg 1 times / day multiple, oral Recommended	unhealthy, 41
Constipation	6 patients	289 mg 1 times / day multiple, oral Recommended	unhealthy, 41

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946	substrate 1,193 inhibitor 2,438	substrate 1,388 inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A 227 CYP2C19 2,057 BCRP 910 P-gp 1,741 OATP1B1 1,079 OATP1B3 961	UGT1A4 399 CYP1A1 389 CYP1A2 1,197 CYP3A5 446 CYP2C8 810 CYP2C19 1,119 CYP2E1 729 FMO3 77 UGT1A1 479 P-gp 2,052 OCT1 393 OCT3 92 OCTN1 55 OCTN2 59 OATP1B1 503 OATP1B3 435

Drug as perpetrator

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Target	Modality	Activity
OATP1B1 1,095	inhibitor 4,027	no
OATP1B3 970	inhibitor 4,027	no
BCRP 985	inhibitor 4,027	yes [IC50 42 uM]
CYP2D6 2,546	inhibitor 4,027	yes [Ki 19 uM]
CYP2C9 2,497	inhibitor 4,027	yes [Ki 31 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP1A2 1,197	substrate 4,014	major	yes (co-administration study)
CYP2C19 1,119	substrate 4,014	minor
CYP2C9 1,193	substrate 4,014	minor
CYP2D6 1,388	substrate 4,014	minor
CYP3A4 1,946	substrate 4,014	minor	weak (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3766	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3766
ChemicalBook	CB7776111	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7776111
eMolecules	536309	https://www.emolecules.com/cgi-bin/more?vid=536309
MolPort	MolPort-001-728-041	https://www.molport.com/shop/molecule-link/MolPort-001-728-041
Selleck Chemicals	Clozapine(Clozaril)	http://www.selleckchem.com/products/Clozapine(Clozaril).html

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PubMed

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Title	Date	PubMed
New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects.	1999 Jun	10435384
Pulmonary embolus possibly associated with clozapine treatment.	1999 May	10332587
High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action.	1999 May	10217294
Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics.	1999 Nov	10669905
[The concept of supersensitivity psychosis. The particular case of clozapine].	1999 Nov-Dec	10668609

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Patents

Sample Use Guides

In Vivo Use Guide

Start with 12.5 mg once daily or twice daily, then increase the total daily dosage in increments of 25 mg to 50 mg per day (if well-tolerated) in order to reach 300 mg to 450 mg per day, in divided doses, by the end of 2 weeks.

Route of Administration: Oral

In Vitro Use Guide

The effects of antipsychotic medication on the energy metabolism of OLN-93 cells were analyzed by adding a vehicle (0.01% HCl, same dissolving solution used to solubilize the antipsychotics), 1 or 10 ug/ml of clozapine to the cell culture for 6 or 24 h.

Show entries

Name

Type

Language

5H-DIBENZO(B,E)(1,4)DIAZEPINE, 8-CHLORO-11-(4-METHYL-1-PIPERAZINYL)-, HYDROCHLORIDE (1:1)

Preferred Name

English

CLOZAPINE HYDROCHLORIDE

Common Name

English

8-CHLORO-11-(4-METHYL-1-PIPERAZINYL)-5H- DIBENZO(B,E)(1,4)DIAZEPINE MONOHYDROCHLORIDE

Systematic Name

English

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Code System

Code

Type

Description

CAS

54241-01-9

PRIMARY

DRUG BANK

DBSALT002286

PRIMARY

PUBCHEM

135524906

PRIMARY

FDA UNII

80862U56A3

PRIMARY

EPA CompTox

DTXSID10969230

PRIMARY

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PARENT (SALT/SOLVATE)


					J60AR2IKIC

CLOZAPINE

SUBSTANCE RECORD


					80862U56A3

CLOZAPINE HYDROCHLORIDE

SMILES

InChI

CNS Activity

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator