917389-32-3

917389-32-3 structure

Name: Letermovir
Chemical Name: 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
CAS Number: 917389-32-3
Molecular Formula: C₂₉H₂₈F₄N₄O₄
Molecular Weight: 572.551
Catalog: Signaling Pathways Anti-infection CMV
Create Date: 2017-07-24 17:33:11
Modify Date: 2024-01-02 18:01:14
Letermovir is a novel inhibitor of CMV, which targets the viral terminase complex and remains active against virus resistant to DNA polymerase inhibitors.

Name	2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
Synonyms	Letermovir Letermovir [INN] 1H09Y5WO1F {(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid 4-Quinazolineacetic acid, 8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-, (4S)- AIC246 (4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid 2-((4S)-8-Fluoro-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-4H-quinazolin-4-yl)acetic acid [(S)-8-fluoro-2-[4-(3-methoxy-phenyl)-piperazin-1-yl]-3-(2-methoxy-5-trifluoromethyl-phenyl)-3,4-dihydro-quinazolin-4-yl]-acetic acid UNII-1H09Y5WO1F

Description	Letermovir is a novel inhibitor of CMV, which targets the viral terminase complex and remains active against virus resistant to DNA polymerase inhibitors.
Related Catalog	Signaling Pathways >> Anti-infection >> CMV Research Areas >> Infection
In Vitro	AIC246 has consistent antiviral efficacy, and there is remarkable selectivity of AIC246 for human cytomegaloviruses[1]. AD169 mutant strains and designated rAIC246-1 and rAIC246-2 are highly resistant to Letermovir (AIC246), with EC50s of 5.6 nM, 1.24 μM, 0.37 μM, respectively. Letermovir inhibits HCMV replication through a specific antiviral mechanism that involves the viral gene product UL56. Letermovir inhibits HCMV replication in cell culture by interfering with the proper cleavage/packaging of HCMV progeny DNA[2]. Letermovir inhibits the current gold standard GCV by more than 400-fold with respect to EC50s (mean, 4.5 nM versus 2 μM) and by more than 2,000-fold with respect to EC90 values (mean, 6.1 nM versus 14.5 μM)[3]. Letermovir in conbination with anti-HCMV drugs causes additive antiviral effects, but there is no interaction between letermovir and anti-HIV drugs[4].
In Vivo	Letermovir (10-100 mg/kg/day, p.o.) leads to a dose-dependent reduction of the HCMV titer in transplanted cells compared to that of the placebo-treated control group using the mouse xenograft model[3].
Cell Assay	Briefly, 5×103 AD169-infected NHDF cells/well are seeded into the wells of 30 96-well microtiter plates. The infection is allowed to proceed under the exposure of 50 nM AIC246 (10×EC50) until a CPE developed in one or more of the compound-treated wells (indicative of resistant virus breakthrough). Noninfected and nontreated cells serve as controls on each plate. Mutant virus amplification is accomplwashed after cultures achieved maximum CPE by the passage of cell-free supernatant virus in the presence of 50 nM AIC246. The resultant AIC246-resistant progeny virus mutants are plaque purified three times by limiting dilutions in the presence of AIC246. The stability of resistance is tested by serially passaging plaque-purified viruses without selective pressure (8 to 10 times).
Animal Admin	Mice (18 to 25 g body weight) are anesthetized, and the Gelfoam sponges are implanted subcutaneously in the dorsoscapular area. After transplantation, mice are randomized and grouped in 10 animals per treatment group. Starting 4 h after transplantation, mice are treated once daily with letermovir for nine consecutive days. Drugs are applied per os by oral gavage. Total administration volume is 10 mL/kg. Mice are sacrificed after 9 days of treatment, and the Gelfoam implants are removed and digested with collagenase at 37°C. After 2 to 3 h, human cells are recovered by centrifugation and resuspended in GM. Subsequently, the isolated cell suspensions are serially diluted and mixed with uninfected NHDF indicator cells and PFU are determined by plaque assays as described above. Virus titers determined from isolated cells are given as PFU/mL.
References	[1]. Marschall M, et al. In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses. Antimicrob Agents Chemother. 2012 Feb;56(2):1135-7. [2]. Goldner T, et al. 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. [3]. Lischka P, et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother. 2010 Mar;54(3):1290-7. [4]. Wildum S, et al. In vitro drug combination studies of Letermovir (AIC246, MK-8228) with approved anti-human cytomegalovirus (HCMV) and anti-HIV compounds in inhibition of HCMV and HIV replication. Antimicrob Agents Chemother. 2015;59(6):3140-8.

Density	1.4±0.1 g/cm3
Boiling Point	706.5±70.0 °C at 760 mmHg
Molecular Formula	C₂₉H₂₈F₄N₄O₄
Molecular Weight	572.551
Flash Point	381.1±35.7 °C
Exact Mass	572.204651
PSA	77.84000
LogP	3.47
Vapour Pressure	0.0±2.4 mmHg at 25°C
Index of Refraction	1.601

Hazard Codes	Xn

917389-30-1

~82%

917389-32-3

Literature: BAYER HEALTHCARE AG Patent: WO2006/133822 A1, 2006 ; Location in patent: Page/Page column 3; 30; 31-32; 36-37 ;

917389-34-5

917389-37-8

917389-32-3

Literature: BAYER HEALTHCARE AG Patent: WO2006/133822 A1, 2006 ; Location in patent: Page/Page column 37 ;

Precursor 0
DownStream 1
791116-51-3

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