REVEFENACIN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C35H43N5O4
Molecular Weight	597.747
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CN(CCN1CCC(CC1)OC(=O)NC2=CC=CC=C2C3=CC=CC=C3)C(=O)C4=CC=C(CN5CCC(CC5)C(N)=O)C=C4

InChI

InChIKey=FYDWDCIFZSGNBU-UHFFFAOYSA-N

InChI=1S/C35H43N5O4/c1-38(34(42)29-13-11-26(12-14-29)25-40-19-15-28(16-20-40)33(36)41)23-24-39-21-17-30(18-22-39)44-35(43)37-32-10-6-5-9-31(32)27-7-3-2-4-8-27/h2-14,28,30H,15-25H2,1H3,(H2,36,41)(H,37,43)

HIDE SMILES / InChI

Molecular Formula	C35H43N5O4
Molecular Weight	597.747
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

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

Description

Revefenacin (trade name Yupelri is a long-acting muscarinic antagonist developed by Mylan Ireland ltd for the treatment of chronic obstructive pulmonary disease (COPD). It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo models, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Muscarinic acetylcholine receptor M3 159	Antagonist 2,778	0.39 nM [Kd]
Muscarinic acetylcholine receptor M1 169	Antagonist 2,778	1.0 nM [Kd]
Muscarinic acetylcholine receptor M2 121	Antagonist 2,778	0.61 nM [Kd]
Muscarinic acetylcholine receptor M4 86	Antagonist 2,778	0.46 nM [Kd]
Muscarinic acetylcholine receptor M5 62	Antagonist 2,778	4.2 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic obstructive pulmonary disease 174	Primary		Approved 8,429	YUPELRI

C_max

Value	Dose	Analyte	Population
0.105 ng/mL	175 μg single, respiratory	REVEFENACIN plasma	Homo sapiens
0.114 ng/mL	175 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
0.309 ng/mL	175 μg single, respiratory	REVEFENACIN plasma	Homo sapiens
0.577 ng/mL	700 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
0.0742 ng/mL	175 μg single, respiratory	THRX-195518 plasma	Homo sapiens
0.178 ng/mL	175 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens
0.178 ng/mL	175 μg single, respiratory	THRX-195518 plasma	Homo sapiens
0.948 ng/mL	700 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
0.0702 ng × h/mL	175 μg single, respiratory	REVEFENACIN plasma	Homo sapiens
0.092 ng × h/mL	175 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
0.161 ng × h/mL	175 μg single, respiratory	REVEFENACIN plasma	Homo sapiens
0.443 ng × h/mL	700 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
0.117 ng × h/mL	175 μg single, respiratory	THRX-195518 plasma	Homo sapiens
0.299 ng × h/mL	175 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens
0.259 ng × h/mL	175 μg single, respiratory	THRX-195518 plasma	Homo sapiens
1.48 ng × h/mL	700 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
23 h	700 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
23.5 h	175 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens
22.3 h	700 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens

F_unbound

Value	Dose	Analyte	Population
29%	175 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
29%	700 μg 1 times / day steady-state, respiratory	REVEFENACIN plasma	Homo sapiens
42%	175 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens
42%	700 μg 1 times / day steady-state, respiratory	THRX-195518 plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418	Other AEs: Cough, Nasopharyngitis...
175 ug 1 times / day steady, respiratory	unhealthy n = 427	Disc. AE: Hypertension...
175 ug 1 times / day steady, respiratory	unhealthy n = 427	Disc. AE: Cough, Bronchiectasis...

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AEs

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AE	Significance	Dose	Population
Bronchitis	1-2	175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418
Dizziness	1-2	175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418
Hypertension	1-2	175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418
Oropharyngeal pain	1-2	175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418
Back pain	2%	175 ug 1 times / day steady, respiratory Recommended	unhealthy, 64 years (range: 41 - 88 years) n = 418

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587 substrate 1,737	inhibitor 1,767	inhibitor 1,852 substrate 1,217	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1,524 CYP2B6 810 CYP2C8 911 CYP2C19 1,478 OATP1B1 788 OATP1B3 706 OAT1 599 OAT3 642 OCT2 647 BCRP 699	CYP3A 191 CYP3A5 395 OATP1B1 406 OATP1B3 350 OAT1 326 OAT2 115 OAT3 339 P-gp 1,537 BCRP 561	CYP1A2 701 CYP2B6 547 CYP3A4/5 124

Drug as perpetrator

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Target	Modality	Activity	Metabolite
BCRP 773	inhibitor 3,277	no
BCRP 773	inhibitor 3,277	no	THRX-195518 1
CYP1A2 1,692	inducer 1,573	no
CYP1A2 1,692	inhibitor 3,277	no
CYP1A2 1,692	inhibitor 3,277	no	THRX-195518 1

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Drug as victim

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Target	Modality	Activity
OAT1 326	substrate 3,367	no
OAT2 115	substrate 3,367	no
OAT3 339	substrate 3,367	no
CYP2D6 1,217	substrate 3,367	yes
CYP3A 191	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626
hERG 1,647	inhibitor 1,626		THRX-195518 1

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY445243	https://www.001chemical.com/chem/864750-70-9
AA Blocks	AA00H1HI	https://www.aablocks.com/goods/Goods/detail?id=AA00H1HI
AbMole Bioscience	M6127	http://www.abmole.com/products/cpdd1221.html
Achemtek	0102-032475	http://www.achemtek.com/864750-70-9-2
Acorn PharmaTech	ACN-051241	http://www.acornpharmatech.com/

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PubMed

Title	Date	PubMed
No data available in table

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of YUPELRI (revefenacin) inhalation solution is one 175 mkg unit-dose vial administered once daily by nebulizer using a mouthpiece.

Route of Administration: Respiratory

In Vitro Use Guide

CHO-K1 cell membrane fractions expressing human recombinant M2 or M3 mAChRs were incubated with [3H]revefenacin (18.5 Ci/mmol), [3H]glycopyrrolate (70 Ci_mmol_1), for 1 hours at 37°C or [3H]tiotropium (70 Ci/mmol) for 4 hours at 37°C. Nonspecific binding was defined in the presence of 10 mkmol/L atropine.

Substance Class	Chemical
Record UNII	G2AE2VE07O
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

REVEFENACIN

Official Name

English

1-(2-(4-((4-CARBAMOYLPIPERIDIN-1-YL)METHYL)-N-METHYLBENZAMIDO)ETHYL)PIPERIDIN-4-YL N-((1,1'-BIPHENYL)-2-YL)CARBAMATE

Systematic Name

English

GSK-1160724

Code

English

TD-4208

Code

English

GSK1160724

Code

English

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Classification Tree

Code System

Code

Anticholinergic Agent

NCI_THESAURUS

C29704

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Code System

Code

Type

Description

FDA UNII

G2AE2VE07O

PRIMARY

DRUG BANK

DB11855

PRIMARY

NCI_THESAURUS

C152200

PRIMARY

USAN

DE-71

PRIMARY

MERCK INDEX

m12116

PRIMARY

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Related Record

Type

Details


					76UB6O122H

ATP-BINDING CASSETTE SUB-FAMILY G MEMBER 2

TRANSPORTER -> SUBSTRATE


					8HOL4T03PN

MUSCARINIC ACETYLCHOLINE RECEPTOR M4

TARGET -> INHIBITOR

Interaction Type:

BINDING

Qualification:

Kd

Amount:

0.46 NANOMOLAR (average)


					W3JX5KZ4V2

MUSCARINIC ACETYLCHOLINE RECEPTOR M3

TARGET -> INHIBITOR

Comments:

In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation.

Interaction Type:

BINDING

Qualification:

Kd

Amount:

0.39 NANOMOLAR (average)


					8E4LAA4357

CYTOCHROME P450 2D6

METABOLIC ENZYME -> SUBSTRATE


					U87RX375T5

MUSCARINIC ACETYLCHOLINE RECEPTOR M2

TARGET -> INHIBITOR

Interaction Type:

BINDING

Qualification:

Kd

Amount:

0.61 NANOMOLAR (average)

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Related Record

Type

Details


					K91V240Q6R

1-((4-(2-HYDROXYETHYL(METHYL)CARBAMOYL)PHENYL)METHYL)PIPERIDINE-4-CARBOXAMIDE

METABOLITE -> PARENT


					A6X64T4LZ4

THRX-195518

METABOLITE ACTIVE -> PARENT

Interaction Type:

MAJOR

Amount:

14.4 % (average)


					I36G7M20DF

1-((4-(2-(4-HYDROXY-1-PIPERIDYL)ETHYL-METHYL-CARBAMOYL)PHENYL)METHYL)PIPERIDINE-4-CARBOXYLIC ACID

METABOLITE -> PARENT


					SES2JJ91YA

1-((4-(2-(4-HYDROXY-1-PIPERIDYL)ETHYLCARBAMOYL)PHENYL)METHYL)PIPERIDINE-4-CARBOXYLIC ACID

METABOLITE -> PARENT


					O6UGY56RDH

1-((4-(2-(4-HYDROXY-1-PIPERIDYL)ETHYL-METHYL-CARBAMOYL)PHENYL)METHYL)PIPERIDINE-4-CARBOXAMIDE

METABOLITE -> PARENT

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Related Record

Type

Details


					G2AE2VE07O

REVEFENACIN

ACTIVE MOIETY

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Name	Property Type	Amount
Biological Half-life	PHARMACOKINETIC	[22 to 74] hours (average)

Tmax	PHARMACOKINETIC	[14 to 41] minutes (average)

Volume of Distribution	PHARMACOKINETIC	218 LITERS (average)

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