Identification

Name
Letermovir
Accession Number
DB12070
Type
Small Molecule
Groups
Approved, Investigational
Description

Letermovir recieved approval from the FDA on November 8th, 2017 for use in prophylaxis of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant patients [6]. It represents the first entry into a new class of CMV anti-infectives, DNA terminase complex inhibitors [3]. Letermovir has recieved both priority and orphan drug status from the FDA. It is currently marketed under the brand name Prevymis [6].

Structure
Thumb
Synonyms
Not Available
External IDs
AIC 246 / AIC-246 / AIC246 / MK-8228
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PrevymisSolution20 mgIntravenousMerck Ltd.2017-12-20Not applicableCanada
PrevymisSolution20 mgIntravenousMerck Ltd.2017-12-20Not applicableCanada
PrevymisTablet, film coated480 mg/1OralMerck Sharp & Dohme Limited2017-11-08Not applicableUs
PrevymisTablet480 mgOralMerck Ltd.2017-12-20Not applicableCanada
PrevymisInjection, solution20 mg/1mLIntravenousMerck Sharp & Dohme Limited2017-11-08Not applicableUs
PrevymisTablet, film coated240 mg/1OralMerck Sharp & Dohme Limited2017-11-08Not applicableUs
PrevymisTablet240 mgOralMerck Ltd.2017-12-20Not applicableCanada
PrevymisInjection, solution20 mg/1mLIntravenousMerck Sharp & Dohme Limited2017-11-08Not applicableUs
Categories
UNII
1H09Y5WO1F
CAS number
917389-32-3
Weight
Average: 572.561
Monoisotopic: 572.20466805
Chemical Formula
C29H28F4N4O4
InChI Key
FWYSMLBETOMXAG-QHCPKHFHSA-N
InChI
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
IUPAC Name
2-[(4S)-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3,4-dihydroquinazolin-4-yl]acetic acid
SMILES
COC1=CC=CC(=C1)N1CCN(CC1)C1=NC2=C(C=CC=C2F)[C@H](CC(O)=O)N1C1=CC(=CC=C1OC)C(F)(F)F

Pharmacology

Indication

For use in prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT) [Label].

Associated Conditions
Pharmacodynamics

Letermovir inhibits the activity of the DNA terminase complex of CMV thereby preventing the cutting of viral DNA into mature length genomes for packaging into viral particles [Label]. Letemovir inhibits the DNA terminase complex with an EC50 of 2.1nM.

Mechanism of action

CMV relies on a DNA terminase complex consisting of multiple subunits (pUL51, pUL56, and pUL89) for processing of viral DNA. Viral DNA is produced in a single repeating strand which is then cut by the DNA terminase complex into individual viral genomes which can then be packaged into mature viral particles [2]. Letemovir inhibits the activity of this complex to prevent production of mature viral genomes and the production of viable viral particles. The exact nature of Letemovir's binding to this complex is not currently known. Initially, the observation of resistance-causing mutations in pUL56 suggested this subunit was the location of Letemovir binding [3]. However, resistance mutations have now been observed in pUL51, pUL56, and pUL89 [4]. It is possible that changes in amino acid sequence in one subunit could result in conformational changes to interacting subunits affecting Letemovir binding or that Letemovir interacts with multiple subunits of the complex but evidence towards either of these distinctions has not yet been seen. pUL89 is known to contain the endonuclease activity of the complex but because all members of the complex are necessary for targeting as well as protection from proteosomal degradation, it is difficult to discern if Letemovir inhibits pUL89's activity directly [5].

TargetActionsOrganism
ATripartite terminase subunit 1
inhibitor
Human cytomegalovirus (strain Merlin)
ATripartite terminase subunit 2
inhibitor
Human cytomegalovirus (strain Merlin)
ATripartite terminase subunit 3
inhibitor
Human cytomegalovirus (strain Merlin)
Absorption

Letermovir has a bioavailability of 94% in healthy subjects when administered without cyclosporin, 35% in HSCT recipients when administered without cyclosporin, and 85% in HSCT recipients when administered with cyclosporin [Label].

Letermovir's Tmax is 45 min to 2.25 h [Label]. Time to steady state has been observed to be 9-10 days.

Taking Letermovir with food increases Cmax by an average of 129.82% (range of 104.35%-161.50%) [Label]. No significant effect on AUC has been observed .

Volume of distribution

The mean steady state volume of distrubution is 45.5L [Label]

Protein binding

Letermovir has been observed to be 99% bound to plasma proteins at concentrations of 0.2-50 mg/L in vitro [Label].

Metabolism

Letermovir undergoes a minor degree of metabolism through UGT1A1/1A3 [Label].

Route of elimination

Letemovir is taken up by the liver through OATP1B1/3 transporters. 93% is excreted in the feces with 70% as the parent drug [Label]. <2% is excreted in the urine.

Half life

The mean terminal half-life was observed to be 12 hours following administration of Letemovir 480 mg IV once daily [Label].

Clearance

The mean clearance is 11.25 L/h in healthy subjects [1]

Toxicity

There is no human data on the safety of Letemovir in pregnancy [Label]. Embryo-fetal toxicity and malformations have been observed in rats at exposures 11 times the human exposure at the recommended human dose (RHD) of Letemovir. No such toxicity was noted in rats at 3 times human exposure at the RHD or in rabbits at values less than human exposure with the RHD. Total litter loss was observed in 21.7% of female rats at 2 times human exposure at RHD. This did not occur at values similar to human exposure at RHD.

No human data is available regarding lactation [Label]. Letemovir has been observed in the milk of lactating rats and in the blood of their nursing pups.

No data is available concerning the effect of Letemovir on human fertility [Label]. Testicular toxicity leading to reduced fertility has been observed in male rats.

No antidote exists for Letemovir overdosage [Label]. The effectiveness of dialysis in clearing plasma of Letemovir is unknown.

Affected organisms
  • Human Cytomegalovirus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbirateroneThe serum concentration of Letermovir can be increased when it is combined with Abiraterone.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Letermovir.
AcetaminophenThe serum concentration of Letermovir can be increased when it is combined with Acetaminophen.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Letermovir.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Letermovir.
AlbendazoleThe serum concentration of Letermovir can be increased when it is combined with Albendazole.
AlclometasoneThe metabolism of Alclometasone can be decreased when combined with Letermovir.
AlfuzosinThe metabolism of Alfuzosin can be decreased when combined with Letermovir.
AlitretinoinThe serum concentration of Alitretinoin can be increased when it is combined with Letermovir.
AllopurinolThe excretion of Allopurinol can be decreased when combined with Letermovir.
Food Interactions
Not Available

References

Synthesis Reference

Humphrey GR, Dalby SM, Andreani T, Xiang B, Luzung MR, Song ZJ, Shevlin M, Christensen M, Belyk KM, Tschaen DM. 2016.Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer Catalyzed Aza-Michael Reaction. Org. Process Res. Dev. 20(6), 1097-1103. DOI: 10.1021/acs.oprd.6b00076

General References
  1. Kropeit D, Scheuenpflug J, Erb-Zohar K, Halabi A, Stobernack HP, Hulskotte EGJ, van Schanke A, Zimmermann H, Rubsamen-Schaeff H: Pharmacokinetics and safety of letermovir, a novel anti-human cytomegalovirus drug, in patients with renal impairment. Br J Clin Pharmacol. 2017 Sep;83(9):1944-1953. doi: 10.1111/bcp.13292. Epub 2017 May 5. [PubMed:28345163]
  2. Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmermann H, Lischka P: The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol. 2011 Oct;85(20):10884-93. doi: 10.1128/JVI.05265-11. Epub 2011 Jul 13. [PubMed:21752907]
  3. Melendez DP, Razonable RR: Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus. Infect Drug Resist. 2015 Aug 5;8:269-77. doi: 10.2147/IDR.S79131. eCollection 2015. [PubMed:26345608]
  4. Chou S: A third component of the human cytomegalovirus terminase complex is involved in letermovir resistance. Antiviral Res. 2017 Dec;148:1-4. doi: 10.1016/j.antiviral.2017.10.019. Epub 2017 Oct 28. [PubMed:29107686]
  5. Neuber S, Wagner K, Goldner T, Lischka P, Steinbrueck L, Messerle M, Borst EM: Mutual Interplay between the Human Cytomegalovirus Terminase Subunits pUL51, pUL56, and pUL89 Promotes Terminase Complex Formation. J Virol. 2017 May 26;91(12). pii: e02384-16. doi: 10.1128/JVI.02384-16. Print 2017 Jun 15. [PubMed:28356534]
  6. FDA Approved Drugs: Letermovir [Link]
External Links
ChemSpider
26352849
ChEMBL
CHEMBL1241951
Wikipedia
Letermovir
AHFS Codes
  • 08:18.08.08 — HIV Protease Inhibitors
FDA label
Download (1.86 MB)
MSDS
Download (22.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedPreventionCytomegalovirus / HCMV Reactivation or HCMV End-Organ Disease1
3CompletedPreventionInfections, Cytomegalovirus / Prevention of CMV Infection or Disease1
3RecruitingPreventionCMV Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous20 mg/1mL
SolutionIntravenous20 mg
TabletOral240 mg
TabletOral480 mg
Tablet, film coatedOral240 mg/1
Tablet, film coatedOral480 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7196086No2004-05-222024-05-22Us
US8513255No2004-05-222024-05-22Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.01 mg/mLALOGPS
logP4.58ALOGPS
logP4.64ChemAxon
logS-4.8ALOGPS
pKa (Strongest Acidic)3.75ChemAxon
pKa (Strongest Basic)7.15ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.84 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity147.44 m3·mol-1ChemAxon
Polarizability55 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenylpiperazines. These are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Phenylpiperazines
Alternative Parents
N-arylpiperazines / Quinazolinamines / Trifluoromethylbenzenes / Aminophenyl ethers / Methoxyanilines / Anisoles / Dialkylarylamines / Phenoxy compounds / Methoxybenzenes / Alkyl aryl ethers
show 12 more
Substituents
Phenylpiperazine / N-arylpiperazine / Quinazolinamine / Quinazoline / Trifluoromethylbenzene / Aminophenyl ether / Methoxyaniline / Anisole / Phenol ether / Phenoxy compound
show 33 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human cytomegalovirus (strain Merlin)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Component of the molecular motor that translocates viral genomic DNA in empty capsid during DNA packaging. Forms a tripartite terminase complex together with TRM2 and TRM3 in the host cytoplasm. Once the complex reaches the host nucleus, it interacts with the capsid portal vertex. This portal forms a ring in which genomic DNA is translocated into the capsid. TRM1 carries an endonuclease activity that plays an important role for the cleavage of concatemeric viral DNA into unit length genomes.
Specific Function
Atp binding
Gene Name
TRM1
Uniprot ID
F5HC79
Uniprot Name
Tripartite terminase subunit 1
Molecular Weight
95810.305 Da
Kind
Protein
Organism
Human cytomegalovirus (strain Merlin)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Component of the molecular motor that translocates viral genomic DNA in empty capsid during DNA packaging. Forms a tripartite terminase complex together with TRM1 and TRM3 in the host cytoplasm. Once the complex reaches the host nucleus, it interacts with the capsid portal vertex. This portal forms a ring in which genomic DNA is translocated into the capsid.
Specific Function
Not Available
Gene Name
TRM2
Uniprot ID
F5HGI9
Uniprot Name
Tripartite terminase subunit 2
Molecular Weight
16977.55 Da
Kind
Protein
Organism
Human cytomegalovirus (strain Merlin)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Component of the molecular motor that translocates viral genomic DNA in empty capsid during DNA packaging. Forms a tripartite terminase complex together with TRM1 and TRM2 in the host cytoplasm. Once the complex reaches the host nucleus, it interacts with the capsid portal vertex. This portal forms a ring in which genomic DNA is translocated into the capsid. TRM3 carries an RNase H-like nuclease activity that plays an important role for the cleavage of concatemeric viral DNA into unit length genomes.
Specific Function
Dna binding
Gene Name
TRM3
Uniprot ID
F5HCU8
Uniprot Name
Tripartite terminase subunit 3
Molecular Weight
77033.575 Da

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A1
Uniprot ID
P22309
Uniprot Name
UDP-glucuronosyltransferase 1-1
Molecular Weight
59590.91 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A3
Uniprot ID
P35503
Uniprot Name
UDP-glucuronosyltransferase 1-3
Molecular Weight
60337.835 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Letermovir FDA label [File]
  2. Letermovir FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inducer
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Monooxygenase activity
Specific Function
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name
CYP3A43
Uniprot ID
Q9HB55
Uniprot Name
Cytochrome P450 3A43
Molecular Weight
57669.21 Da

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Organic anion transmembrane transporter activity
Specific Function
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter.
Gene Name
ABCC2
Uniprot ID
Q92887
Uniprot Name
Canalicular multispecific organic anion transporter 1
Molecular Weight
174205.64 Da

Drug created on October 20, 2016 15:18 / Updated on September 25, 2018 17:45