COPANLISIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H28N8O4
Molecular Weight	480.5196
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

COC1=C(OCCCN2CCOCC2)C=CC3=C1N=C(NC(=O)C4=CN=C(N)N=C4)N5CCN=C35

InChI

InChIKey=PZBCKZWLPGJMAO-UHFFFAOYSA-N

InChI=1S/C23H28N8O4/c1-33-19-17(35-10-2-6-30-8-11-34-12-9-30)4-3-16-18(19)28-23(31-7-5-25-20(16)31)29-21(32)15-13-26-22(24)27-14-15/h3-4,13-14H,2,5-12H2,1H3,(H2,24,26,27)(H,28,29,32)

HIDE SMILES / InChI

Molecular Formula	C23H28N8O4
Molecular Weight	480.5196
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
Optical Activity	NONE

Description

Copanlisib, developed by Bayer, is a phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity. Copanlisib inhibits the activation of the PI3K signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents. Copanlisib is currently under Phase II/III clinical trials for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
PI3-kinase p110-beta subunit 31	Inhibitor 8,297	3.7 nM [IC50]
PI3-kinase p110-delta subunit 43	Inhibitor 8,297	0.7 nM [IC50]
PI3-kinase p110-alpha subunit 41	Inhibitor 8,297	0.5 nM [IC50]
PI3-kinase p110-gamma subunit 32	Inhibitor 8,297	6.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Relapsed follicular lymphoma 3	Primary		Approved 8,429	ALIQOPA

C_max

Value	Dose	Co-administered	Analyte	Population
463 ng/mL	60 mg 1 times / week steady-state, intravenous		COPANLISIB plasma	Homo sapiens
447 μg/L	0.8 mg/kg 1 times / week multiple, intravenous		COPANLISIB plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
1570 ng × h/mL	60 mg 1 times / week steady-state, intravenous		COPANLISIB plasma	Homo sapiens
1280 μg × h/L	0.8 mg/kg 1 times / week multiple, intravenous		COPANLISIB plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
39.1 h	60 mg 1 times / week steady-state, intravenous		COPANLISIB plasma	Homo sapiens
35.6 h	0.8 mg/kg 1 times / week multiple, intravenous		COPANLISIB plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)	DLT: Alanine aminotransferase increased, Aspartate aminotransferase increased...
60 mg 3 times / month steady, intravenous Recommended\|MTD	unhealthy, adult	Disc. AE: Hyperglycemia, Neutropenia...
60 mg 3 times / month steady, intravenous Recommended\|MTD	unhealthy, adult	Disc. AE: Thrombocytopenia, Neutropenia...

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AEs

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AE	Significance	Dose	Population
Alanine aminotransferase increased	grade 3, 1 patient DLT, Disc. AE	1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)
Left ventricular systolic dysfunction	grade 3, 1 patient DLT, Disc. AE	1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)
Acidosis lactic	grade 4, 1 patient DLT, Disc. AE	1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)
Anion gap	grade 4, 1 patient DLT, Disc. AE	1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)
Aspartate aminotransferase increased	grade 4, 1 patient DLT, Disc. AE	1.2 mg/kg 3 times / month steady, intravenous Highest studied dose	unhealthy, 62 years (range: 35–86 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587	inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 UGT 35 MRP2 383 BSEP 402 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT1 512 OCT2 647 P-gp 1,461 BCRP 699 MATE1 306 MATE2 263	CYP3A 191 CYP3A4/5 85 CYP1A1 349

Drug as perpetrator

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Target	Modality	Activity
BSEP 403	inhibitor 3,277	no
CYP1A2 1,692	inhibitor 3,277	no
CYP2A6 739	inhibitor 3,277	no
CYP2B6 1,001	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP1A1 349	substrate 3,367	yes
CYP3A4/5 85	substrate 3,367	yes
CYP3A 191	substrate 3,367	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA0039IF	https://www.aablocks.com/goods/Goods/detail?id=AA0039IF
Aaron Chemicals	AR003AA7	http://www.aaronchem.com/1032568-63-0
abcr GmbH	AB457959	http://www.abcr.de/shop/en/AB457959
AbMole Bioscience	M2436	http://www.abmole.com/products/bay-80-6946.html
Achemtek	0102-013863	http://www.achemtek.com/1032568-63-0

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PubMed

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Title	Date	PubMed
BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110α and p110δ activities in tumor cell lines and xenograft models.	2013 Nov	24170767
Preliminary results of a phase II study of single agent Bay 80-6946, a Novel PI3K inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma.	2014 Feb	24852792

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Patents

Sample Use Guides

In Vivo Use Guide

60 mg in solution administered intravenously on Days 1, 8 and 15 of each 28-day treatment cycle

Route of Administration: Oral

In Vitro Use Guide

Several breast cancer, endometrial cancer, and hematologic tumor cell lines were particularly sensitive to Copanlisib, with IC50 values less than 10nmol/L

Substance Class	Chemical
Record UNII	WI6V529FZ9
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

COPANLISIB

Official Name

English

2-AMINO-N-(7-METHOXY-8-(3-(MORPHOLIN-4-YL)PROPOXY)-2,3-DIHYDROIMIDAZO(1,2-C)QUINAZOLIN-5-YL(PYRIMIDINE-5-CARBOXAMIDE

Common Name

English

COPANLISIB [MI]

Common Name

English

BAY-80-6946

Code

English

2-AMINO-N-(7-METHOXY-8-(3-MORPHOLIN-4-YLPROPOXY)-2,3-DIHYDROIMIDAZO(1,2-C)QUINAZOLIN-5-YL)PYRIMIDINE-5-CARBOXAMIDE

Systematic Name

English

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Classification Tree

Code System

Code

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

Designated/Approved

FDA ORPHAN DRUG

463314

Other antineoplastic agents

WHO-ATC

L01XX61

Designated

FDA ORPHAN DRUG

811321

Designated

FDA ORPHAN DRUG

552416

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Code System

Code

Type

Description

SMS_ID

100000170809

PRIMARY

NCI_THESAURUS

C96796

PRIMARY

PUBCHEM

24989044

PRIMARY

MERCK INDEX

m12036

PRIMARY

WIKIPEDIA

Copanlisib

PRIMARY

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Related Record

Type

Details


					W421JK3CPA

COPANLISIB HYDROCHLORIDE HYDRATE

SALT/SOLVATE -> PARENT


					9DX651UO0D

CYTOCHROME P450 1A1

METABOLIC ENZYME -> SUBSTRATE

Interaction Type:

MINOR

Amount:


					XGE1085C9Q

PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT BETA ISOFORM

TARGET -> INHIBITOR


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> SUBSTRATE

Comments:

90% OF METABOLISM

Interaction Type:

MAJOR


					03ZI7RZ52O

COPANLISIB HYDROCHLORIDE

SALT/SOLVATE -> PARENT

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Related Record

Type

Details


					QY9D7067E8

2-AMINO-N-(2,3-DIHYDRO-8-HYDROXY-7-METHOXYIMIDAZO(1,2-C)QUINAZOLIN-5-YL)-5-PYRIMIDINECARBOXAMIDE

METABOLITE -> PARENT

Comments:

(DEALKYLATION BY CYP3A4), The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

5.61 % [1.74 to 9.53] (average)
(IN FECES), 0.15 % (RANGE: 0.04-0.32 %, IN URINE), PERCENT OF DOSE


					RTW1LKQ7TC

2-AMINO-N-(8-(3-(FORMYL(2-HYDROXYETHYL)AMINO)PROPOXY)-2,3-DIHYDRO-7-METHOXYIMIDAZO(1,2-C)QUINAZOLIN-5-YL)-5-PYRIMIDINECARBOXAMIDE

METABOLITE -> PARENT

Comments:

(DEALKYLATION BY CYP3A4), The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

[<2] % (limits)
(IN URINE AND FECES), PERCENT OF DOSE


					QYB71X85N4

2-AMINO-N-(2,3-DIHYDRO-8-(3-((2-HYDROXYETHYL)AMINO)PROPOXY)-7-METHOXYIMIDAZO(1,2-C)QUINAZOLIN-5-YL)-5-PYRIMIDINECARBOXAMIDE

METABOLITE -> PARENT

Comments:

(DEALKYLATION BY CYP3A4), The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

7.32 % [5.61 to 11.6] (average)
(IN FECES), 0.32 % (RANGE: 0-0.62 %, IN URINE), PERCENT OF DOSE


					7D3BZM3BQN

3-((5-(2-AMINOPYRIMIDINE-5-CARBOXAMIDO)-7-METHOXY-2,3-DIHYDROIMIDAZO(1,2-C)QUINAZOLIN-8-YL)OXY)PROPANOIC ACID

METABOLITE -> PARENT

Comments:

(DEALKYLATION BY CYP3A4), The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

11.6 % [9.91 to 13] (average)
(IN FECES), 0.34 % (RANGE: 0.10-0.52 %, IN URINE), PERCENT OF DOSE


					GC91Z6YS52

2-AMINO-N-(8-(3-HYDROXYPROPOXY)-7-METHOXY-2,3-DIHYDROIMIDAZO(1,2-C)QUINAZOLIN-5-YL)PYRIMIDINE-5-CARBOXAMIDE

METABOLITE -> PARENT

Comments:

(DEALKYLATION BY CYP3A4), The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; URINE

Amount:

[<2] % (limits)
(IN URINE, AND FECES), PERCENT OF DOSE

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Related Record

Type

Details


					WI6V529FZ9

COPANLISIB

ACTIVE MOIETY

Comments:

The six healthy male volunteers received a single i.v. infusion of 12 mg copanlisib (2.76 MBq (14C)copanlisib) in a total volume of 40 mL as a 1-h infusion in the morning, 1-h after a light breakfast. 5 Caucasians and 1 Asian with an age 54.8 +/- 5.2 yeas (mean +/- SD, range: 47-61 years) and a BMI of 24.8 kg/m^2. Non-smokers and reported at the most light alcohol use.

Interaction Type:

AMOUNT EXCRETED

Qualification:

FECAL; PLASMA; URINE

Amount:

30.1 % [16.8 to 37.9] (average)
(IN FECES), 15.0 % (RANGE: 9.52-18.7 %, IN URINE), PERCENT OF DOSE

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	39.1 hours (average)

Volume of Distribution	PHARMACOKINETIC	12.4 Liters/Kilogram (average)

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator