NALDEMEDINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H34N4O6
Molecular Weight	570.6356
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(C)(NC(=O)C1=C(O)[C@@H]2OC3=C(O)C=CC4=C3[C@@]25CCN(CC6CC6)[C@H](C4)[C@]5(O)C1)C7=NC(=NO7)C8=CC=CC=C8

InChI

InChIKey=AXQACEQYCPKDMV-RZAWKFBISA-N

InChI=1S/C32H34N4O6/c1-30(2,29-33-27(35-42-29)18-6-4-3-5-7-18)34-28(39)20-15-32(40)22-14-19-10-11-21(37)25-23(19)31(32,26(41-25)24(20)38)12-13-36(22)16-17-8-9-17/h3-7,10-11,17,22,26,37-38,40H,8-9,12-16H2,1-2H3,(H,34,39)/t22-,26+,31+,32-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C32H34N4O6
Molecular Weight	570.6356
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Naldemedine (Symproic) is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids. Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB). Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Mu opioid receptor 221	Antagonist 2,778		161.08 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Opioid-induced constipation 8	Secondary		Approved 8,429	Symproic
opioid-induced constipation 2	Secondary		Approved 8,429	SYMPROIC

C_max

Value	Dose	Co-administered	Analyte	Population
1.98 ng/mL	0.1 mg single, oral		NALDEMEDINE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
11.6 ng × h/mL	0.1 mg single, oral		NALDEMEDINE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.3 h	0.1 mg single, oral		NALDEMEDINE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
100 mg single, oral Highest studied dose	healthy, 21.8 years n = 6	Other AEs: Abdominal pain, Diarrhea...
30 mg 1 times / day multiple, oral Highest studied dose	healthy, 28.3 years n = 9	Other AEs: Abdominal discomfort, Diarrhea...
0.2 mg 1 times / day steady, oral Recommended	unhealthy, adult n = 1163	Disc. AE: Abdominal pain, Diarrhea...

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AEs

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AE	Significance	Dose	Population
Abdominal pain	16.7%	100 mg single, oral Highest studied dose	healthy, 21.8 years n = 6
Diarrhea	16.7%	100 mg single, oral Highest studied dose	healthy, 21.8 years n = 6
Abdominal discomfort	11.1%	30 mg 1 times / day multiple, oral Highest studied dose	healthy, 28.3 years n = 9
Diarrhea	11.1%	30 mg 1 times / day multiple, oral Highest studied dose	healthy, 28.3 years n = 9
Colitis	0.1% Disc. AE	0.2 mg 1 times / day steady, oral Recommended	unhealthy, adult n = 1163

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1,737	inhibitor 1,767 substrate 1,037	inhibitor 1,852 substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2A6 707 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 CYP2E1 882 CYP3A4/5 278 CYP4A11 21 OATP1B1 788 OATP1B3 706 OCT1 512 OCT2 647 OAT1 599 OAT3 642 BCRP 699 P-gp 1,461	CYP1A2 1,054 CYP2A6 543 CYP2B6 664 CYP2C8 693 CYP2E1 667 CYP2C19 991 UGT1A3 422 UGT1A1 418 UGT1A4 347 UGT1A6 307 UGT1A9 380 UGT2B4 249 UGT2B7 389 UGT2B15 203 UGT2B17 213 OATP1B1 406 OATP1B3 350 OCT1 327 OCT2 355 OAT1 326 OAT3 339 BCRP 561 P-gp 1,537	UGT1A6 34 UGT2B7 14 UGT1A3 9 CYP1A2 701 CYP2B6 547

Drug as perpetrator

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Target	Modality	Activity
CYP2A6 739	inhibitor 3,277	low or no [IC50 >20 uM]
CYP2B6 1,001	inhibitor 3,277	low or no [IC50 >20 uM]
CYP2D6 1,891	inhibitor 3,277	low or no [IC50 >20 uM]
CYP2E1 970	inhibitor 3,277	low or no [IC50 >20 uM]
CYP4A11 25	inhibitor 3,277	low or no [IC50 >20 uM]

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Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	no
CYP1A2 1,054	substrate 3,367	no
CYP2A6 543	substrate 3,367	no
CYP2B6 664	substrate 3,367	no
CYP2C8 693	substrate 3,367	no

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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	AA00JS9Z	https://www.aablocks.com/goods/Goods/detail?id=AA00JS9Z
Chem Scene	CS-0016072	http://www.chemscene.com/916072-89-4.html
Compound Cloud	54732242
Compound Cloud	56837137
MedChem Express	HY-19627	https://www.medchemexpress.com/naldemedine.html

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PubMed

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Title	Date	PubMed
Formulary Drug Review: Naldemedine.	2017 Jul	29276274
Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy.	2018	29391826
Efficacy of Treatments for Opioid-Induced Constipation: Systematic Review and Meta-analysis.	2018 Oct	29374616

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Patents

Sample Use Guides

In Vivo Use Guide

Administration (2.1): • Alteration of analgesic dosing regimen prior to initiating SYMPROIC is not required • Patients receiving opioids for less than 4 weeks may be less responsive to SYMPROIC • Discontinue SYMPROIC if treatment with the opioid pain medication is also discontinued Dosage (2.2): • The recommended dosage of SYMPROIC is 0.2 mg orally once daily with or without food.

Route of Administration: Oral

In Vitro Use Guide

In binding assays, the IC50 and Ki values of S-297995 (Naldemedine) monotosylate for rat mu opioid receptor were 3.21 and 1.40 nM, respectively. S-297995 exhibited antagonistic activity with IC50 and Kb values for rat mu opioid receptor of 161.08 and 0.56 nM, respectively.

Substance Class	Chemical
Record UNII	03KSI6WLXH
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

NALDEMEDINE

Official Name

English

NALDEMEDINE [MI]

Common Name

English

NALDEMEDINE [USAN]

Common Name

English

17-(CYCLOPROPYLMETHYL)-6,7-DIDEHYDRO-4,5A-EPOXY-3,6,14-TRIHYDROXY-N-(2-(3-PHENYL-1,2,4-OXADIAZOL-5-YL)PROPAN-2-YL)MORPHINAN-7-CARBOXAMIDE

Common Name

English

Naldemedine [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Peripheral opioid receptor antagonists

WHO-ATC

A06AH05

Established Pharmacologic Class

NDF-RT

N0000175691

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Code System

Code

Type

Description

INN

9484

PRIMARY

DAILYMED

03KSI6WLXH

PRIMARY

MERCK INDEX

m12021

PRIMARY

CAS

916072-89-4

PRIMARY

RXCUI

1876597

PRIMARY

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Related Record

Type

Details


					V1N8F1RVVO

NALDEMEDINE TOSYLATE

SALT/SOLVATE -> PARENT


					2BJ58BX78W

KAPPA-TYPE OPIOID RECEPTOR

TARGET -> INHIBITOR

Comments:

Used recombinant human kappa-opioid receptor (expressed in HEK-293 cells), U-50488H as an agonist, and guanosine-5’-O-(3-(35S)thio) triphosphate ((35S)-GTP.GAMMA.S) as a ligand

Interaction Type:

ANTAGONIST

Qualification:

Kb

Amount:

0.436 NANOMOLAR (average)


					1PE72K8X46

MU-TYPE OPIOID RECEPTOR

TARGET -> INHIBITOR

Comments:

Used recombinant human mu-opioid receptor (expressed in CHO-K1 cells), DAMGO as an agonist, and guanosine-5’-O-(3-(35S)thio) triphosphate ((35S)-GTP.GAMMA.S) as a ligand

Interaction Type:

ANTAGONIST

Qualification:

Kb

Amount:

0.5 NANOMOLAR (average)