LETERMOVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C29H28F4N4O4
Molecular Weight	572.5506
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC(=CC=C1)N2CCN(CC2)C3=NC4=C(C=CC=C4F)[C@H](CC(O)=O)N3C5=CC(=CC=C5OC)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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26345608
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/27345658 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

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytomegalovirus 1 Target ID: CHEMBL613134 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26345608	Inhibitor 8297		2.5 nM [EC50]
Tripartite terminase subunit UL28 homolog 1 Target ID: F5HC79 Gene ID: 3077457.0 Gene Symbol: UL56 Target Organism: Human cytomegalovirus (strain Merlin) (HHV-5) (Human herpesvirus 5) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26259791 \| https://www.ncbi.nlm.nih.gov/pubmed/21752907 \| https://www.ncbi.nlm.nih.gov/pubmed/24189264	Inhibitor 8297		3.1 nM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
cytomegalovirus infection 1 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209939Orig1s000,209940Orig1s000lbl.pdf	Preventing		Approved 8429	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 2017
Cytomegalovirus infection 6 Sources: https://clinicaltrials.gov/ct2/show/NCT02137772	Preventing		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
27.33 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28722153/	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

Value	Dose	Analyte	Population
105.66 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28722153/	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

T_1/2

Value	Dose	Analyte	Population
13.05 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28675594/	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28722153/	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.95% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/28722153/	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

Dose	Population	Adverse events
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
480 mg 1 times / day multiple, oral Recommended Dose: 480 mg, 1 times / day Route: oral Route: multiple Dose: 480 mg, 1 times / day Co-administed with:: cyclosporine Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf Page: 209939Orig1s000,209940Orig1s000MedR.pdf - p.87	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf Page: 209939Orig1s000,209940Orig1s000MedR.pdf - p.87	Disc. AE: CMV infection... AEs leading to discontinuation/dose reduction: CMV infection (6.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf Page: 209939Orig1s000,209940Orig1s000MedR.pdf - p.87
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/	healthy n = 6 Health Status: healthy Sex: F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/	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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/

AEs

AE	Significance	Dose	Population
Septic shock	0.2% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Abdominal pain	0.5% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Blood creatinine increased	0.5% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Venoocclusive liver disease	0.5% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Graft versus host disease	0.8% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Vomiting	0.8% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Acute myeloid leukemia recurrent	1.1% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
Nausea	1.6% 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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/29211658/
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 Co-administed with:: cyclosporine Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf Page: 209939Orig1s000,209940Orig1s000MedR.pdf - p.87	unhealthy, median age 53 years n = 373 Health Status: unhealthy Condition: CMV infection Age Group: median age 53 years Sex: M+F Population Size: 373 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf Page: 209939Orig1s000,209940Orig1s000MedR.pdf - p.87
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/	healthy n = 6 Health Status: healthy Sex: F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/	healthy n = 6 Health Status: healthy Sex: F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/
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: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/	healthy n = 6 Health Status: healthy Sex: F Population Size: 6 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209939Orig1s000,209940Orig1s000MedR.pdf https://pubmed.ncbi.nlm.nih.gov/28675594/

Sourcing

Vendor/Aggregator	ID	URL
AA Blocks	AA00GT9F	https://www.aablocks.com/goods/Goods/detail?id=AA00GT9F
Aaron Chemicals	AR00GU17	http://www.aaronchem.com/917389-32-3
Achemtek	0102-013766	http://www.achemtek.com/917389-32-3
Ambeed	A236700	https://www.ambeed.com/products/917389-32-3.html
ApexBio Technology	A3550	http://www.apexbt.com/letermovir.html
BLD Pharm	BD631005	http://www.bldpharm.com/products/917389-32-3.html
BioCrick	BCC1700	http://www.biocrick.com/Letermovir-BCC1700.html
CSNpharm	CSN18574	https://www.csnpharm.com/products/letermovir.html
Chem Scene	CS-1571	http://www.chemscene.com/917389-32-3.html
Chemspace	CSSB00161189425	https://chem-space.com/CSSB00161189425
DAOGE BIOPHARMA	DG21-14059	https://www.daogechem.com/product/917389-32-3.html
DC Chemicals	DC9402	http://www.dcchemicals.com/product_show-Letermovir.html
Excenen	EX-A1871	https://www.excenen.com/searchresultlist.php?id=917389-32-3
Hairui	LECQ009	http://www.hairuichem.com/en/product/917389-32-3.html
Lab Network	LN01327924	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01327924
MedChem Express	HY-15233	https://www.medchemexpress.com/letermovir.html
MuseChem	I005468	https://www.musechem.com/product/I005468.html
Smolecule	S532821	http://www.smolecule.com/products/s532821
Synblock Inc	SB16739	http://www.synblock.com/product/917389-32-3.html
THE BioTek	bt-273112	https://www.thebiotek.com/product/inhibitors/bt-273112

PubMed

Title	Date	PubMed
In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246.	2010 Mar	20047911
In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses.	2012 Feb	22106211

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

Letermovir revealed potent antiviral activity against 17 HCMV clinical isolates, with 50% effective concentrations (EC50s) in the low nanomolar range (0.8-3.1nM).

Name

Type

Language

LETERMOVIR

Official Name

English

AIC246

Code

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 [WHO-DD]

Common Name

English

letermovir [INN]

Common Name

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