OMACETAXINE MEPESUCCINATE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H39NO9
Molecular Weight	545.6213
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

COC(=O)C[C@](O)(CCCC(C)(C)O)C(=O)O[C@H]1[C@H]2C3=CC4=C(OCO4)C=C3CCN5CCC[C@]25C=C1OC

InChI

InChIKey=HYFHYPWGAURHIV-JFIAXGOJSA-N

InChI=1S/C29H39NO9/c1-27(2,33)8-5-10-29(34,16-23(31)36-4)26(32)39-25-22(35-3)15-28-9-6-11-30(28)12-7-18-13-20-21(38-17-37-20)14-19(18)24(25)28/h13-15,24-25,33-34H,5-12,16-17H2,1-4H3/t24-,25-,28+,29-/m1/s1

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Description

Omacetaxine mepesuccinate (trade name Synribo) formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML). It is a natural ester of the alkaloid cephalotaxine from Cephalotaxus harringtonia, now manufactured by hemi-synthesis. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
60S ribosomal protein L3 3	Antagonist 2,849

Conditions

Condition	Modality	Highest Phase	Product
Chronic myeloid leukemia, chronic phase 3	Primary	Approved 8,583	SYNRIBO
Chronic myeloid leukemia, accelerated phase 3	Primary	Approved 8,583	SYNRIBO
Unknown 2,596

C_max

Value	Dose	Analyte	Population
25.1 ng/mL	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
36.2 ng/mL	1.25 mg/m² 2 times / day multiple, subcutaneous	OMACETAXINE plasma	Homo sapiens
28.6 ng/mL	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
25.1 ng/mL	1.25 mg/m² single, subcutaneous	[NO STEREO] OMACETAXINE MEPESUCCINATE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
136.2 ng × h/mL	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
188 ng × h/mL	1.25 mg/m² 2 times / day multiple, subcutaneous	OMACETAXINE plasma	Homo sapiens
188 ng × h/mL	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
136.2 ng × h/mL	1.25 mg/m² single, subcutaneous	[NO STEREO] OMACETAXINE MEPESUCCINATE plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
6.96 h	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
7.03 h	1.25 mg/m² 2 times / day multiple, subcutaneous	OMACETAXINE plasma	Homo sapiens
14.6 h	1.25 mg/m² single, subcutaneous	OMACETAXINE plasma	Homo sapiens
6.96 h	1.25 mg/m² single, subcutaneous	[NO STEREO] OMACETAXINE MEPESUCCINATE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
50%	single, unknown		OMACETAXINE plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)	DLT: Haematemesis, Pulmonary aspergillosis... Other AEs: Anasarca...
3 mg/m2 1 times / day multiple, subcutaneous	unhealthy, 57 years (range: 20–79 years)	DLT: Hyperglycaemia, Diabetic hyperosmolar coma...
1.25 mg/m2 2 times / day multiple, subcutaneous Recommended	unhealthy, 59 years	Disc. AE: Thrombocytopenia, Alanine aminotransferase increased... Other AEs: Thrombocytopenia, Thrombocytopenia...
1.25 mg/m2 2 times / day multiple, subcutaneous Recommended	unhealthy, 59 years	Disc. AE: Bone marrow failure, Sepsis...
1.25 mg/m2 2 times / day multiple, subcutaneous Recommended	unhealthy, 59 years	Other AEs: Anemia, Anemia...

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AEs

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AE	Significance	Dose	Population
Anasarca	grade 3, 1 patient	5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)
Haematemesis	grade 3, 1 patient DLT	5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)
Scalp pain	grade 3, 1 patient DLT	5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)
Skin rash	grade 3, 1 patient DLT	5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)
Pulmonary aspergillosis	grade 4, 1 patient DLT	5 mg/m2 1 times / day multiple, subcutaneous MTD	unhealthy, 57 years (range: 20–79 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252		inhibitor 2,507	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A 70 CYP2C19 2,057 P-gp 1,741	CYP 303 P-gp 2,052	CYP1A 59

Drug as perpetrator

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Target	Modality	Activity	Metabolite
P-gp 1,932	inhibitor 4,027	no
CYP3A4 2,633	inhibitor 4,027	strong [Inhibition 10 uM]
CYP1A 122	inhibitor 4,027	weak [Inhibition 10 uM]
CYP2C19 2,141	inhibitor 4,027	weak [Inhibition 10 uM]	DMHHT 3
CYP2D6 2,546	inhibitor 4,027	weak [Inhibition 10 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
CYP 303	substrate 4,014	no
P-gp 2,052	substrate 4,014	yes

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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
AA Blocks	AA00BBK4	https://www.aablocks.com/goods/Goods/detail?id=AA00BBK4
Aaron Chemicals	AR00BCBW	http://www.aaronchem.com/24316-19-6
abcr GmbH	AB479786	http://www.abcr.com/shop/en/AB479786
AbMole Bioscience	M3942	http://www.abmole.com/products/cephalotaxine.html
Achemtek	0104-028087	http://www.achemtek.com/24316-19-6

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PubMed

Title	Date	PubMed
A formal total synthesis of (-)-cephalotaxine.	1999 Jul	10434399

Patents

Sample Use Guides

In Vivo Use Guide

Unknown

Route of Administration: Unknown

In Vitro Use Guide

Unknown

Show entries

Name

Type

Language

OMACETAXINE MEPESUCCINATE

Official Name

English

HOMOHARRINGTONINE

Preferred Name

English

CEPHALOTAXINE 4-METHYL (2R)-2-HYDROXY-2-(4-HYDROXY-4-METHYLPENTYL)BUTANEDIOATE (ESTER)

Common Name

English

HOMOHARRINGTONINE [MI]

Common Name

English

CEPHALOTAXINE, 4-METHYL (2R)-2-HYDROXY-2-(4-HYDROXY-4-METHYLPENTYL)BUTANEDIOATE (ESTER)

Common Name

English

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Classification Tree

Code System

Code

Designated/Approved

FDA ORPHAN DRUG

218205

Designated

FDA ORPHAN DRUG

272608

Cell Differentiating Agent

NCI_THESAURUS

C1934

Other antineoplastic agents

WHO-ATC

L01XX40

Withdrawn

EU-Orphan Drug

EU/3/04/224

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Code System

Code

Type

Description

FDA UNII

6FG8041S5B

PRIMARY

DRUG CENTRAL

4677

PRIMARY

EPA CompTox

DTXSID0045678

PRIMARY

SMS_ID

100000115463

PRIMARY

NSC

141633

PRIMARY

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ACTIVE MOIETY


					84MI6OYN4Z

OMACETAXINE

SALT/SOLVATE (PARENT)


					563OX5661H

OMACETAXINE MEPESUCCINATE HYDROCHLORIDE

SUBSTANCE RECORD


					6FG8041S5B

OMACETAXINE MEPESUCCINATE

SMILES

InChI

CNS Activity

Originator

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