| Identification | Back Directory | [Name]
Darunavir | [CAS]
206361-99-1 | [Synonyms]
D03656
TMC-114
UIC-94017
Darunavir
Darunavir (usan/inn)
Darunavir( UIC-94017,TMC-114)
(3R,3AS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3
(3R,3AS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamate
(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-phenylbutan-2-yl]carbamate
[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenyl-methyl)propyl]carabamic Acid (3R,3aS,6aR)-Hexahydrofuro[2,3-b]-furan-3-yl Ester
[(1S,2R)-3-[[(4-Aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenyl-methyl)propyl]carabamic Acid (3R,3aS,6aR)-Hexahydrofuro[2,3-β]-furan-3-yl Ester
[(3R,3aS,6aR)-2,3,3a,4,5,6a-Hexahydrofuro[5,4-b]furan-3-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate | [EINECS(EC#)]
606-590-1 | [Molecular Formula]
C27H37N3O7S | [MDL Number]
MFCD09260006 | [MOL File]
206361-99-1.mol | [Molecular Weight]
547.66 |
| Chemical Properties | Back Directory | [Appearance]
White Amorphous Solid | [Melting point ]
74-760C | [density ]
1.34±0.1 g/cm3(Predicted) | [storage temp. ]
-20°C Freezer | [solubility ]
Soluble in DMSO (>25 mg/ml) | [form ]
powder | [pka]
11.43±0.46(Predicted) | [color ]
white to beige | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. |
| Hazard Information | Back Directory | [Chemical Properties]
White Amorphous Solid | [Uses]
Second generation HIV-1-protease inhibitor; structurally similar to amprenavir. Antiviral | [Definition]
ChEBI: An N,N-disubstituted benzenesulfonamide bearing an unsubstituted amino group at the 4-position, used for the treatment of HIV infection. A second-generation HIV protease inhibitor, darunavir was designed to form robust
interactions with the protease enzyme from many strains of HIV, including those from treatment-experienced patients with multiple resistance mutations to other protease inhibitors. | [Description]
Darunavir is the latest weapon in the arsenal of agents to combat human
immunodeficiency virus type 1(HIV-1). As an HIV-1 protease inhibitor, its mechanism
of action involves blocking the cleavage of the gag and gag–pol polyproteins
into functional proteins essential for the production of infectious progeny
virus; the result is the production of immature, noninfectious viral particles.
Compared to predecessor HIV protease inhibitors, darunavir retains activity
against resistant stains, a critical factor with the continual emergence of multidrug-
resistant (MDR) mutants. Despite experiencing a 13-fold reduction in binding
to MDR HIV-1 protease, this binding is 1.5 orders of magnitude tighter than
the first-generation protease inhibitors. Furthermore, darunavir exhibits less than
a 10-fold decrease in susceptibility in cell culture against 90% of 3309 clinical
isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,
ritonavir, saquinavir, and tipranavir. In contrast, darunavir-resistant viruses display
limited susceptibility to only tipranavir, suggesting limited cross-resistance
between these two protease inhibitors. To avoid the issues of the peptide-based
protease inhibitors, darunavir has evolved from a structure-based design effort to
minimize peptidic features and reduce molecular weight and complexity. | [Originator]
Tibotec/J&J (US) | [Brand name]
Prezista | [Acquired resistance]
Darunavir is less affected than other protease inhibitors
by mutations to resistance, but subgroups with more than
10 cumulative mutations show a >10-fold (median value)
decrease in susceptibility. The major resistance mutations
occur at positions 50 (150V), 54 (I50M/L), 76 (L76V) and
84 (I84V) of the protease gene. | [Pharmaceutical Applications]
A synthetic compound formulated as the ethanolate for oral
use in combination with ritonavir. | [Biochem/physiol Actions]
Darunavir has been sanctioned by the food and drug administration (FDA) as the first treatment of drug-resistant human immunodeficiency virus (HIV). | [Pharmacokinetics]
Oral absorption: c. 82%
Cmax 600 mg once daily + ritonavir 100
mg twice daily:
c. 6500 μg/L
Cmin 600 mg oral + ritonavir
100 mg twice daily:
c. 3578 μg/L
Plasma half-life: c. 15 h
Volume of distribution: c. 131 L
Plasma protein binding: c. 95%
A single 600 mg dose given orally in combination with ritonavir
100 mg every 12 h increased the systemic exposure of
darunavir approximately 14-fold. The relative bioavailability
is 30% lower when administered with food in the presence of
low-dose ritonavir. Distribution into human CSF, semen or
breast milk has not yet been determined.
At least three oxidative metabolites, mediated predominantly
through CYP3A4, have been identified in humans;
all are at least 10-fold less active than the parent compound
against HIV. Around 80% and 14% of the dose is found in the
feces and urine, respectively. It should be used with caution
in mild–moderate hepatic impairment and avoided in patients
with more severe impairment. | [Clinical Use]
Treatment of HIV infection (in combination with other antiretroviral drugs) | [Side effects]
In phase III studies the most common adverse events were
diarrhea, nausea, headache and nasopharyngitis. Patients coinfected
with hepatitis B or C did not have a higher incidence
of adverse events. | [Synthesis]
Several routes to the synthesis
of darunavir have been reported utilizing the chiral
hexahydro-furo[2,3-b]furan-3-ol carbonate 12 and
several chiral syntheses of bisfuranol 12 have been disclosed
as well. One route that has been performed on kilogram
scale is highlighted in the scheme. Thus 2,3-Oisopropylidene-
glyceraldehyde 5 was stirred with dimethyl
malonate at RT for 3 h in tetrahydrofuran followed by addition
of pyridine and heating to 45oC. Then acetic anhydride
was added at 45oC over 4h and stirred at that temperature for
12 h. Concentration of the reaction followed by basic
workup and extraction with toluene and solvent swap to
methanol gave the products as a 23.6% solution in methanol.
Nitromethane was added to this methanol solution followed
by the addition of DBU over 30 min keeping the reaction
temperature below 25oC. Stirring the reaction for an additional
3 h afforded intermediate 7. The reaction was cooled to 0oC and sodium methoxide was added dropwise over 30
min After stirring the reaction for 30 min, the reaction was
added slowly over 1h to conc. H2SO4 in methanol at 0oC
while ensuring the temperature did not exceed 10oC. This
cooled reaction mixture (0oC) was then added to a vigorously
stirred mixture of ethyl acetate and 1N sodium hydrogen
carbonate at 0oC. The organic layer was separated, washed
with brine and concentrated to give the residue containing a
mixture of 8 and 9. This mixture was dissolved in methanol
then water and potassium hydroxide were added and the resulting
mixture was heated at reflux for 2 h. The reaction
was cooled to 35oC and acetic acid was added and the resulting
mixture concentrated. Additional acetic acid was added
and stirred at room temperature for 2 h. The mixture was
concentrated, diluted with water and extracted with ethylacetate.
The ethylacetate layer was washed with 1N sodium bicarbonate
three times and the organic layer was concentrated
and diluted with isopropanol. The isopropanol mixture was
then heated to 60-70oC and further evaporation of isopropanol
under reduced pressure to a concentrated volume with
cooling to 0oC over 4-5 h, allowed for the crystallization of
product 10. After filtration and drying, the intermediate lactone
10 was dissolved in THF and treated over 30 min with a
solution of lithium borohydride in THF. The reaction was
warmed to 50oC over 1 h and stirred at that temperature for
2h. The resulting suspension was cooled to -10oC and conc.
HCl was added slowly over 4h, while maintaining the temperature
below 0oC. Solvent swap was done by concentrating
to a small volume and addition of ethyl acetate and further
concentration of the solvent with continuous addition of ethylacetate.
Following this procedure, when the final ratio of
THF:ethylacetate reached 4:1 ratio, the mixture was cooled
to 0oC and filtered off while washing the filter cake with
more ethylacetate. Concentration of the filtrate to dryness
gave the hexahydro-furo [2,3-b]furan-3-ol 11 which was
confirmed by NMR and chiral gas chromatography. Carbonate
intermediate 12 was prepared in 66% yield by treating 11
with disuccinimidyl carbonate at RT for 3h in the presence
of triethylamine. Since the process scale synthesis of
darunavir has not been disclosed, the latest reported synthesis
is highlighted. The commercially available epoxide
13 was mixed with isobutyl amine in isopropanol at RT and
refluxed for 6h. The reaction was concentrated and purified
by chromatography to provide amine 15 (99%). p-Nitrophenyl
sulfonyl chloride was added to a mixture of the amine 15
in dichloromethane and saturated aqueous bicarbonate at RT
and stirred for 12 h to give sulfonamide 16 in 96% yield after
purification. Hydrogenation of 16 with 10% Pd/C under 1
atm hydrogen for 11h at room temperature gave aniline 17 in
95% yield. The BOC group was removed by treating 17 with
TFA in dichloromethane and the resulting amine was reacted
with carbonate 12 in the presence of triethylamine for 3h to
provide the desired darunavir (II) in 89% yield.
| [target]
HIV Protease | [Drug interactions]
Potentially hazardous interactions with other drugs
Antibacterials: rifabutin concentration increased -
reduce dose of rifabutin; darunavir concentration
reduced by rifampicin - avoid.
Anticoagulants: avoid with apixaban and rivaroxaban
Antidepressants: possibly reduced concentration of
paroxetine and sertraline; darunavir concentration
reduced by St John’s wort - avoid.
Antimalarials: concentration of lumefantrine increased;
possibly increases concentration of quinine
Antipsychotics: possibly increases concentration of
aripiprazole (reduce dose of aripiprazole); possibly
increases quetiapine concentration - avoid.
Antivirals: avoid with boceprevir or telaprevir; take
didanosine 1 hour before or 2 hours after darunavir
administration; concentration reduced by efavirenz
- adjust dose; concentration of both drugs increased
with indinavir and simeprevir - avoid with simeprevir;
concentration reduced by lopinavir, also concentration
of lopinavir increased - avoid; concentration of
maraviroc increased, consider reducing dose of
maraviroc; concentration of paritaprevir increased
and paritaprevir reduces darunavir concentration;
concentration reduced by saquinavir; increased risk of
rash with raltegravir; avoid with telaprevir.
Cytotoxics: possibly increases bosutinib concentration,
avoid or reduce dose of bosutinib; possibly increases
everolimus concentration - avoid; possibly increases
ibrutinib concentration - reduce ibrutinib dose.
Ergot alkaloids: increased risk of ergotism - avoid.
Lipid-lowering drugs: possibly increased risk of
myopathy with atorvastatin and rosuvastatin, reduce
dose of rosuvastatin; possibly increases pravastatin
concentration; avoid with lomitapide; avoid with
simvastatin.1
Orlistat: absorption of darunavir possibly reduced.
Ranolazine: possibly increases ranolazine
concentration - avoid. | [Metabolism]
Darunavir is metabolised by oxidation by the cytochrome
P450 system (mainly the isoenzyme CYP3A4), with at
least 3 metabolites showing some antiretroviral activity.
About 80% of a dose is excreted in the faeces, with 41.2%
of this as unchanged drug; 14% is excreted in the urine | [storage]
Store at -20°C | [References]
Koh et al. (2003), Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI UIC-94017 (YMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro; Antimicrob. Agents Chemother., 47 2123
Surleraux et al. (2005), Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor; J. Med. Chem., 48 1813
Beck et al. (2020), Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model; Comput. Struct. Biotechnol. J, 18 784
Khan et al. (2020), Identification of chymotrypsin-like protease inhibitors of SARS-VCoV-2 via integrated computational approach; J. Biomol.Struct. Dyn., 39 2607
De Meyers et al. (2020), Lack of antiviral activity of darunavir against SARS-CoV-2; J. Infect. Dis, 97 7
Kim et al. (2020), Use of Darunavir-Cobicistat as a Treatment Option for Critically Ill Patients with SARS-CoV-2 Infection; Yonsei Med. J., 61 826 |
| Questions And Answer | Back Directory | [AIDS treatment]
Darunavir is a new kind of non peptide anti retroviral protease inhibitors in AIDS therapy. It is first developed by the Johnson pharmaceutical Iceland branch, Tibotec. It is of the highest bioavailability in the 6 protease inhibitors (saquinavir, ritonavirvir, indinavir, naphthalene nelfinavir, amprenavir and ABT378/r). It acts by blocking the formation of new and mature virus particles from the surface of the infected host cells and inhibiting the virus's protease. When the product is used for a long time, it usually can reduce the HIV virus vector in blood, increase the count of CD4 cells, reduce the chance of HIV infection, improve the quality of life and prolong life. It is suitable for adults who are infected with the HIV virus but have no effect on the use of existing antiretroviral drugs. The drug must be combined with the use of low doses of ritonavir or other antiretroviral agents, in order to improve the efficacy. The antiviral activity in vitro can be evaluated by being against acute and chronic infected lymphocytes and lymphocytes in peripheral blood. The IC50 is 0.012 to 0.08 mmol/ L for acute infected cells and 0.41 mmol/L for chronic infected cells. For oral administration, recommended dose is 1,200mg once and twice per day. The doseshould be reduced for patients with mild to moderate liver dysfunction and those with renal dysfunction. The adverse reaction of darunavir is mainly gastrointestinal reaction, flushing, itching and perioral numbness, depression, mood disorders, taste disorder etc. This product is not recommended for patients with moderate to severe liver dysfunction. Because of the sulfonamides in this component, it is prohibited for those who are allergic to sulfanilamide and any component in the prescription of this product.
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