PASIREOTIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C58H66N10O9
Molecular Weight	1047.2062
Optical Activity	UNSPECIFIED
Defined Stereocenters	7 / 7
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

[H][C@@]12C[C@H](CN1C(=O)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](CC4=CC=C(OCC5=CC=CC=C5)C=C4)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC6=CNC7=C6C=CC=C7)NC(=O)[C@@H](NC2=O)C8=CC=CC=C8)OC(=O)NCCN

InChI

InChIKey=VMZMNAABQBOLAK-DBILLSOUSA-N

InChI=1S/C58H66N10O9/c59-27-13-12-22-46-52(69)64-47(30-38-23-25-42(26-24-38)76-36-39-16-6-2-7-17-39)53(70)66-49(31-37-14-4-1-5-15-37)57(74)68-35-43(77-58(75)61-29-28-60)33-50(68)55(72)67-51(40-18-8-3-9-19-40)56(73)65-48(54(71)63-46)32-41-34-62-45-21-11-10-20-44(41)45/h1-11,14-21,23-26,34,43,46-51,62H,12-13,22,27-33,35-36,59-60H2,(H,61,75)(H,63,71)(H,64,69)(H,65,73)(H,66,70)(H,67,72)/t43-,46+,47+,48-,49+,50+,51+/m1/s1

HIDE SMILES / InChI

Molecular Formula	C58H66N10O9
Molecular Weight	1047.2062
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	7 / 7
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Pasireotide is a synthetic long-acting cyclic hexapeptide with somatostatin-like activity. It is marketed as a diaspartate salt called Signifor, indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. SIGNIFOR is an injectable cyclohexapeptide somatostatin analogue. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (ssts). Pasireotide binds and activates the hsst receptors resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Somatostatin receptor 1 3	Agonist 2,678	9.3 nM [IC50]
Somatostatin receptor 2 6	Agonist 2,678	1.0 nM [IC50]
Somatostatin receptor 3 3	Agonist 2,678	1.5 nM [IC50]
Somatostatin receptor 5 5	Agonist 2,678	0.16 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cushing’s disease 13	Primary		Approved 8,429	SIGNIFOR

C_max

Value	Dose	Analyte	Population
8.23 ng/mL	20 mg 1 times / 4 weeks multiple, intramuscular	PASIREOTIDE plasma	Homo sapiens
17.3 ng/mL	40 mg 1 times / 4 weeks multiple, intramuscular	PASIREOTIDE plasma	Homo sapiens
16.2 ng/mL	60 mg 1 times / 4 weeks multiple, intramuscular	PASIREOTIDE plasma	Homo sapiens
7.19 ng/mL	20 mg single, intramuscular	PASIREOTIDE plasma	Homo sapiens
10.3 ng/mL	40 mg single, intramuscular	PASIREOTIDE plasma	Homo sapiens
17 ng/mL	60 mg single, intramuscular	PASIREOTIDE plasma	Homo sapiens
5.9 ng/mL	60 mg single, subcutaneous	PASIREOTIDE plasma	Homo sapiens
38.7 ng/mL	0.6 mg 2 times / day steady-state, subcutaneous	PASIREOTIDE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
4090 ng × h/mL	60 mg single, subcutaneous		PASIREOTIDE plasma	Homo sapiens
161.1 ng × h/mL	0.6 mg 2 times / day steady-state, subcutaneous		PASIREOTIDE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
12 h	60 mg single, subcutaneous		PASIREOTIDE plasma	Homo sapiens
4.4 h	0.6 mg 2 times / day steady-state, subcutaneous		PASIREOTIDE plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
1500 ug single, subcutaneous Highest studied dose	healthy, 18–40 years
750 ug 2 times / day steady, subcutaneous Highest studied dose	healthy, 18–40 years
0.9 mg 2 times / day multiple, subcutaneous Recommended	healthy, 27 years	Disc. AE: Xanthoma...
0.6 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years	Disc. AE: Diarrhea, Nausea...
0.9 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years	Disc. AE: Diarrhea, Nausea...

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AEs

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AE	Significance	Dose	Population
Xanthoma	1 patient Disc. AE	0.9 mg 2 times / day multiple, subcutaneous Recommended	healthy, 27 years
Cholelithiasis	1.2% Disc. AE	0.6 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years
Diarrhea	1.2% Disc. AE	0.6 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years
Fatigue	1.2% Disc. AE	0.6 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years
Hepatic enzyme increased	1.2% Disc. AE	0.6 mg 2 times / day steady, subcutaneous Recommended	unhealthy, 40 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737	inducer 389 inhibitor 1,767	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,461 UGT1A1 204 MRP2 383 BSEP 402 CYP2B6 810 OATP1B1 788 OATP1B3 706 CYP1A2 1,524 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A4/5 278 K+ channels 70 L-type Ca2+ channels 28 Nav1.5 97 BCRP 699 OCT1 512 OATP2B1 123	P-gp 1,537 BCRP 561 OCT1 327 OATP1B1 406 OATP1B3 350 OATP2B1 104 CYP3A5 395	CYP1A2 701 CYP2B6 547 CYP2C8 168 CYP2C19 293 CYP3A 129 CYP1A1 108 CYP1B1 51 CYP2J2 3 P-gp 257 MRP2 111 UGT1A1 69

Drug as perpetrator

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Target	Modality	Activity
BCRP 773	inhibitor 3,277	no
CYP1A1 218	inducer 1,573	no
CYP1A2 1,692	inducer 1,573	no
CYP1B1 67	inducer 1,573	no
CYP2B6 1,001	inducer 1,573	no

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Drug as victim

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Target	Modality	Activity	Clinical evidence
P-gp 1,537	substrate 3,367	likely	yes (co-administration study)
BCRP 561	substrate 3,367	no
OATP1B1 406	substrate 3,367	no
OATP1B3 350	substrate 3,367	no
OATP2B1 104	substrate 3,367	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
Nav1.5 100	inhibitor 1,626
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
AA Blocks	AA00C6E9	https://www.aablocks.com/goods/Goods/detail?id=AA00C6E9
Achemtek	0102-014407	http://www.achemtek.com/396091-73-9
Alsachim	3608	http://www.alsachim.com/product-C6134-glo.bal-view.html
BioCrick	BCC5300	http://www.biocrick.com/Pasireotide-BCC5300.html
Chem Scene	CS-2328	http://www.chemscene.com/396091-73-9.html

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PubMed

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Title	Date	PubMed
SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs.	2002 Oct	12239124
Functional activity of the multiligand analog SOM230 at human recombinant somatostatin receptor subtypes supports its usefulness in neuroendocrine tumors.	2004	15477717
New aspects in the diagnosis and treatment of Cushing disease.	2006	16809932
Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways.	2010 Jan	19910453
Ligand-dependent mechanisms of sst2A receptor trafficking: role of site-specific phosphorylation and receptor activation in the actions of biased somatostatin agonists.	2011 Jun	21493671

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Patents

Sample Use Guides

In Vivo Use Guide

Recommended initial dosage is either 0.6 mg or 0.9 mg by subcutaneous injection twice a day; recommended dosage range is 0.3 mg to 0.9 mg twice a day

Route of Administration: Other

In Vitro Use Guide

Primary cultures from normal human and rat adrenals were incubated with 10-100 nM Pasireotide with and without 10nM ACTH. Dose-response studies with 1 nM-1 uM Pasireotide were performed on rat adrenals. Cortisol/corticosterone levels in medium were measured after 4 and 24h. Pasireotide (10nM) significantly increased corticosteroid levels after 24h incubation in both human (36.4 ± 0.43 ng/well vs 27.7 ± 3.17 ng/well, p<0.05) and rat (16.2 ± 1.16 ng/well vs 11.6 ± 0.92 ng/well p<0.05) adrenals; lesser effects were observed with 100 nM Pasireotide (33.4 ± 2.59 ng/well vs 27.7 ± 3.17 ng/well p<0.05; 13.4 ± 0.82 ng/well vs 11.6 ± 0.92 ng/well, N.S. vs baseline secretion for human and rat adrenals, respectively). Dose-response curves confirmed maximal effect at 10nM Pasireotide.

Substance Class	Chemical
Record UNII	98H1T17066
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

PASIREOTIDE

Official Name

English

pasireotide [INN]

Common Name

English

CYCLO((4R)-4-(2-AMINOETHYLCARBAMOYLOXY)-L-PROLYL-L-PHENYLGLYCYL-D-TRYPTOPHYL-L-LYSYL-4-O-BENZYL-L-TYROSYL-L-PHENYLALANYL-)

Common Name

English

PASIREOTIDE [VANDF]

Common Name

English

PASIREOTIDE [MI]

Common Name

English

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Classification Tree

Code System

Code

Somatostatin and analogues

WHO-VATC

QH01CB05

Therapeutic Hormone

NCI_THESAURUS

C62799

Positive

EU-Orphan Drug

EU/3/09/671

Designated/Withdrawn

FDA ORPHAN DRUG

188804

Designated/Approved

FDA ORPHAN DRUG

288709

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Code System

Code

Type

Description

MESH

C517782

PRIMARY

DRUG BANK

DB06663

PRIMARY

DRUG CENTRAL

4329

PRIMARY

PUBCHEM

9941444

PRIMARY

IUPHAR

2018

PRIMARY

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Related Record

Type

Details


					6E20216Q0L

SOMATOSTATIN

PARENT -> DERIVATIVE

Amount:


					I4P76SY3N4

PASIREOTIDE DIASPARTATE

SALT/SOLVATE -> PARENT

Amount:


					04F55A7UZ3

PASIREOTIDE PAMOATE

SALT/SOLVATE -> PARENT

Amount:


					G49RZO51ZC

OATP-B

TRANSPORTER -> NON-SUBSTRATE

Amount:


					8X85ZJG6XJ

SOMATOSTATIN RECEPTOR TYPE 5

TARGET -> AGONIST

Amount:

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Related Record

Type

Details


					98H1T17066

PASIREOTIDE

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	0.43 Liters/Kilogram (average)

Tmax	PHARMACOKINETIC	[0.25 to 0.5] hours (average)	SC INJECTION

Biological Half-life	PHARMACOKINETIC	12 hours (average)

SMILES

InChI

CNS Activity

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