U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C29H28F4N4O4
Molecular Weight 572.5517
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LETERMOVIR

SMILES

COc1cccc(c1)N2CCN(CC2)C3=Nc4c(cccc4F)[C@]([H])(CC(=O)O)N3c5cc(ccc5OC)C(F)(F)F

InChI

InChIKey=FWYSMLBETOMXAG-QHCPKHFHSA-N
InChI=1S/C29H28F4N4O4/c1-40-20-6-3-5-19(16-20)35-11-13-36(14-12-35)28-34-27-21(7-4-8-22(27)30)23(17-26(38)39)37(28)24-15-18(29(31,32)33)9-10-25(24)41-2/h3-10,15-16,23H,11-14,17H2,1-2H3,(H,38,39)/t23-/m0/s1

HIDE SMILES / InChI

Molecular Formula C29H28F4N4O4
Molecular Weight 572.5517
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment:: https://www.ncbi.nlm.nih.gov/pubmed/26259791

Letermovir (AIC246 or MK-8228), a 3,4-dihydro-quinazoline- 4-yl-acetic acid derivative, is the prototype viral terminase complex inhibitor that is most advanced in its clinical development. The novel compound was initially developed by AiCuris. In April 2011, the drug was granted orphan drug designation for prevention of CMV disease by the European Commission. In August 2011, the US Food and Drug Administration granted it a fast track designation. In 2012, the results of Phase IIb clinical trials using letermovir in bone marrow transplant patients were presented at various international meetings, and the data were subsequently published in 2014.42 It`s continued clinical development is currently undertaken in agreement with Merck. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. It targets the UL56 subunit of the viral terminase complex. Letermovir is currently in Phase III development.

Originator

Curator's Comment:: # Bayer

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
2.5 nM [EC50]
Target ID: F5HC79
Gene ID: 3077457
Gene Symbol: UL56
Target Organism: Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5)
3.10000000000000009 nM [EC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Preventing
PREVYMIS

Approved Use

PREVYMIS™ is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT)

Launch Date

1510012800000
Preventing
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
27.33 μg/mL
480 mg single, intravenous
dose: 480 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
15.88 μg/mL
240 mg 1 times / day steady-state, intravenous
dose: 240 mg
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
1361 ng/mL
60 mg 1 times / day steady-state, oral
dose: 60 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
[NO STEREO] LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
105.66 μg × h/mL
480 mg single, intravenous
dose: 480 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
33.61 μg × h/mL
240 mg 1 times / day steady-state, intravenous
dose: 240 mg
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
7121 ng × h/mL
60 mg 1 times / day steady-state, oral
dose: 60 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
[NO STEREO] LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
13.05 h
480 mg single, intravenous
dose: 480 mg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
28.31 h
240 mg 1 times / day steady-state, intravenous
dose: 240 mg
route of administration: Intravenous
experiment type: STEADY-STATE
co-administered:
LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: FASTED
14.71 h
60 mg 1 times / day steady-state, oral
dose: 60 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
[NO STEREO] LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
0.95%
60 mg 1 times / day steady-state, oral
dose: 60 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
[NO STEREO] LETERMOVIR plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Disc. AE: Nausea, Acute myeloid leukemia recurrent...
AEs leading to
discontinuation/dose reduction:
Nausea (1.6%)
Acute myeloid leukemia recurrent (1.1%)
Graft versus host disease (0.8%)
Vomiting (0.8%)
Venoocclusive liver disease (0.5%)
Blood creatinine increased (0.5%)
Abdominal pain (0.5%)
Septic shock (0.2%)
Sources:
480 mg 1 times / day multiple, oral
Recommended
Dose: 480 mg, 1 times / day
Route: oral
Route: multiple
Dose: 480 mg, 1 times / day
Sources:
unhealthy, median age 53 years
Health Status: unhealthy
Age Group: median age 53 years
Sex: M+F
Sources:
Disc. AE: CMV infection...
AEs leading to
discontinuation/dose reduction:
CMV infection (6.2%)
Sources:
960 mg 1 times / day single, intravenous
Highest studied dose
Dose: 960 mg, 1 times / day
Route: intravenous
Route: single
Dose: 960 mg, 1 times / day
Sources:
healthy
Other AEs: Vomiting, Vessel puncture site pain...
Other AEs:
Vomiting (grade 3, 16.7%)
Vessel puncture site pain (grade 1-2, 50%)
Vessel puncture site hematoma (grade 1-2, 16.7%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Septic shock 0.2%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Abdominal pain 0.5%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Blood creatinine increased 0.5%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Venoocclusive liver disease 0.5%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Graft versus host disease 0.8%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Vomiting 0.8%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Acute myeloid leukemia recurrent 1.1%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
Nausea 1.6%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
unhealthy, median age 53 years
CMV infection 6.2%
Disc. AE
480 mg 1 times / day multiple, oral
Recommended
Dose: 480 mg, 1 times / day
Route: oral
Route: multiple
Dose: 480 mg, 1 times / day
Sources:
unhealthy, median age 53 years
Health Status: unhealthy
Age Group: median age 53 years
Sex: M+F
Sources:
Vessel puncture site hematoma grade 1-2, 16.7%
960 mg 1 times / day single, intravenous
Highest studied dose
Dose: 960 mg, 1 times / day
Route: intravenous
Route: single
Dose: 960 mg, 1 times / day
Sources:
healthy
Vessel puncture site pain grade 1-2, 50%
960 mg 1 times / day single, intravenous
Highest studied dose
Dose: 960 mg, 1 times / day
Route: intravenous
Route: single
Dose: 960 mg, 1 times / day
Sources:
healthy
Vomiting grade 3, 16.7%
960 mg 1 times / day single, intravenous
Highest studied dose
Dose: 960 mg, 1 times / day
Route: intravenous
Route: single
Dose: 960 mg, 1 times / day
Sources:
healthy
PubMed

PubMed

TitleDatePubMed
In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246.
2010 Mar
In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses.
2012 Feb
Patents

Sample Use Guides

Letermovir oral or intravenous (IV) formulation will be administered once daily for up to 14 weeks after transplant. The dose will be 240 mg once daily for participants receiving concomitant cyclosporin A and 480 mg once daily for participants not receiving cyclosporin A. Intravenous infusion will be administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets.
Route of Administration: Other
Letermovir revealed potent antiviral activity against 17 HCMV clinical isolates, with 50% effective concentrations (EC50s) in the low nanomolar range (0.8-3.1nM).
Substance Class Chemical
Created
by admin
on Sat Jun 26 13:06:07 UTC 2021
Edited
by admin
on Sat Jun 26 13:06:07 UTC 2021
Record UNII
1H09Y5WO1F
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LETERMOVIR
INN   USAN   WHO-DD  
INN   USAN  
Official Name English
AIC246
Code English
LETERMOVIR [WHO-DD]
Common Name English
(4S)-2-(8-FLUORO-2-(4-(3-METHOXYPHENYL)PIPERAZIN-1-YL)-3-(2-METHOXY-5-(TRIFLUOROMETHYL)PHENYL)-3,4-DIHYDROQUINAZOLIN-4-YL)ACETIC ACID
Systematic Name English
4-QUINAZOLINEACETIC ACID, 8-FLUORO-3,4-DIHYDRO-2-(4-(3-METHOXYPHENYL)-1-PIPERAZINYL)-3-(2-METHOXY-5-(TRIFLUOROMETHYL)PHENYL)-, (4S)-
Common Name English
MK-8228
Code English
2-((4S)-8-FLUORO-2-(4-(3-METHOXYPHENYL)PIPERAZIN-1-YL)-3-(2-METHOXY-5-(TRIFLUOROMETHYL)PHENYL)-4H-QUINAZOLIN-4-YL)ACETIC ACID
Systematic Name English
AIC-246
Code English
LETERMOVIR [JAN]
Common Name English
LETERMOVIR [INN]
Common Name English
AIC 246
Code English
LETERMOVIR [USAN]
Common Name English
PREVYMIS
Brand Name English
LETERMOVIR [MI]
Common Name English
LETERMOVIR [ORANGE BOOK]
Common Name English
Classification Tree Code System Code
WHO-ATC J05AX18
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
NCI_THESAURUS C281
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
EU-Orphan Drug EU/3/12/999
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
NDF-RT N0000193800
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
FDA ORPHAN DRUG 340211
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
Code System Code Type Description
DRUG CENTRAL
5262
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
LACTMED
Letermovir
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
EPA CompTox
917389-32-3
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
MERCK INDEX
M12055
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
DRUG BANK
DB12070
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
WIKIPEDIA
LETERMOVIR
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
CAS
917389-32-3
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
ChEMBL
CHEMBL1241951
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
EVMPD
SUB90389
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
FDA UNII
1H09Y5WO1F
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
PUBCHEM
45138674
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
RXCUI
1988648
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
NCI_THESAURUS
C115099
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
INN
9384
Created by admin on Sat Jun 26 13:06:08 UTC 2021 , Edited by admin on Sat Jun 26 13:06:08 UTC 2021
PRIMARY
Related Record Type Details
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> INHIBITOR
TRANSPORTER -> SUBSTRATE
METABOLIC ENZYME -> SUBSTRATE
MINOR
TRANSPORTER -> SUBSTRATE
MINOR
TRANSPORTER -> SUBSTRATE
MINOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
BINDER->LIGAND
BINDING
TRANSPORTER -> INHIBITOR
METABOLIC ENZYME -> INDUCER
METABOLIC ENZYME -> INDUCER
TRANSPORTER -> INHIBITOR
EXCRETED UNCHANGED
AMOUNT EXCRETED
FECAL
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> INHIBITOR
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Tmax PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC INTRAVENOUS ADMINISTRATION

DOSE

blood-to-plasma ratio PHARMACOKINETIC