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AMPRENAVIR

Basic information Safety Supplier Related

AMPRENAVIR Basic information

Product Name:
AMPRENAVIR
Synonyms:
  • KVX-478
  • AGENERASE
  • AMPRENAVIR
  • 141W94
  • PROZEI
  • 141W94, KVX-478, Agenerase, Prozei,
  • Carbamic acid, (1S,2R)-3-(4-aminophenyl)sulfonyl(2-methylpropyl)amino-2-hydroxy-1-(phenylmethyl)propyl-, (3S)-tetrahydro-3-furanyl ester
  • Angenerase
CAS:
161814-49-9
MF:
C25H35N3O6S
MW:
505.63
EINECS:
827-179-5
Product Categories:
  • Inhibitor
  • peptides
  • Anti-viral Compounds
  • Anti-virals
  • Inhibitors
  • API
  • Intermediates & Fine Chemicals
  • Non-nucleoside Reverse Transcriptase
  • Pharmaceuticals
Mol File:
161814-49-9.mol
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AMPRENAVIR Chemical Properties

Melting point:
72-74°C
Density 
1.30±0.1 g/cm3(Predicted)
storage temp. 
-20°C
solubility 
DMSO: soluble20mg/mL, clear
pka
11.54±0.46(Predicted)
form 
powder
color 
white to beige
optical activity
[α]/D +8 to +12°, c = 0.5 in methanol
InChIKey
YMARZQAQMVYCKC-OEMFJLHTSA-N
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Safety Information

RIDADR 
3077
WGK Germany 
3
HS Code 
29350090
Hazardous Substances Data
161814-49-9(Hazardous Substances Data)
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AMPRENAVIR Usage And Synthesis

Description

Amprenavir was launched as Agenerase in the US for the treatment of AIDS patients in combination with approved agent antiretroviral nucleoside analogs. It is the fifth non-peptidic inhibitor of HIV-1 protease to be marketed in this indication after the last approved Neflinavir. Amprenavir, designed via a structure-based process, is the smallest molecule in the 《navir》 class and exhibits a reduced peptidic character. An improved process for preparation comprising four steps from a (1S, 2R)-2-hydroxy-3-aminopropylcarbamate has been developed. Amprenavir is a potent inhibitor of HIV-1 aspartyl protease (Ki = 0.6nM), an enzyme required by the virus to cleave pro-form polyproteins to structural proteins during the last stage in the replication process. The compound displays good oral bioavailability in humans and penetrates the CNS, which is an important advantage in long-term treatment. Its plasma half-life is approximately 10h. Treatment with Amprenavir in combination with nucleoside analog reverse transcriptase inhibitors considerably decreases viral load and restores CD4+ T-cell counts in patients with HIV infection.

Chemical Properties

Off-White to Pale Yellow

Originator

Vertex Pharm (US)

Uses

A selective HIV protease inhibitor. An analogue of Ritonavir

Uses

Protease inhibitor, anti-HIV agent

Indications

Amprenavir (Agenerase) is administered twice daily, providing the patient with an advantage over other protease inhibitors that must be taken more frequently (e.g., indinavir, saquinavir). Common side effects of am-prenavir include nausea, vomiting, diarrhea, and perioral paraesthesias. Rash occurs in approximately 20 to 30% of patients and can be mild or severe (Stevens- Johnson syndrome).

Manufacturing Process

(1-Oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester may be synthesized from available starting materials (see B. E. Evans et al., J. Org. Chem., 50, p.4615 (1985)). The amprenavir may be preparated with the next steps.
1. (1-Benzyl-3-isobutylaminopropyl)-carbamic acid t-butylester. A solution of 4.1 g of epoxide (1-oxiranyl-2-phenylethyl)-carbamic acid t-butyl ester in 30 ml of ethanol was treated with 22.4 ml of isobutylamine and heated under reflux for 1 h. The mixture was concentrated to yield the title compound as a white solid which was used without subsequent purification.
2. To a solution of the above compound (2.5 g, 7.43 mmol) in CH2Cl2 (50 ml) was added triethylamine (2.1 ml, 14.9 mmol) followed by addition of benzyl chloroformate (1.2 ml, 8.1 mmol). The mixture was allowed to stir at ambient temperature for 6 h. The solution was diluted with 1 L of CH2Cl2 and washed with water. The organics were dried over anhydrous MgSO4, concentrated under reduced pressure, then purified via silica gel chromatography. Gradient solvent system: CH2Cl2 followed by 3:97 methanol/CH2Cl2. (3-t- Butoxycabonylamino-4-phenylbutyl)-isobutylcarbamic acid benzyl ester (2.97 g) was obtained as a colorless oil. TLC: Rf= 0.14, 3:97 methanol/CH2Cl2. 3. BOC - protecting group was removed as followed: to a solution of 1.5 g (3.187 mmol) of the above compound of in ethyl acetate (25 ml) at - 20°C was bubbled anhydrous HCl gas for 10 min. The ice bath was removed and after an additional 15 min the reaction mixture was sparged with nitrogen, then concentrated in vacuo to provide 1.29 g of deprotected product as a white solid which was used directly for the next reaction TLC: Rf= 0.14, 10% methanol/CH2Cl2.
4. Isobutyl[4-phenyl-(S)-3-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]- carbamic acid benzyl ester. To a solution of 1.077 g of the above resultant crude compound (2.647 mmol) in acetonitrile (10 ml) was added sequentially at ambient temperature under an atmosphere of nitrogen, 1.61 ml (9.263 mmol) of diisopropylethylamine and 910 mg (3.97 mmol) of the Nsuccinimidyl-( S)-3-tetrahydrocfuryl carbonate. The last one was prepared from phosgene and (S)-(+)-3-hydroxytetrahydrofuran by usual procedure. After stirring for 3 h, an additional 223 mg (0.973 mmol) of the N-succinimidyl-(S)- 3-tetrahydrocfuryl carbonate was added. The mixture was stirred for 16 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, 0.5 N HCl, saturated sodium bicarbonate, saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel column chromatography using a gradient 10% to 25% ethyl acetate in CH2Cl2 eluent to yield 1.025 g of the title product as a white solid. TLC: Rf= 0.10, 10% ethyl acetate/CH2Cl2.
5. A solution of 872 mg (1.799 mmol) isobutyl[4-phenyl-(S)-3- tetrahydrofuran-3-yl-oxycarbonylamino)-butyl]-carbamic acid benzyl ester in (10 ml) of ethyl alcohol was added, at ambient temperature under a nitrogen atmosphere, to a slurry of 87 mg (10% by weight) of 10% palladium on carbon in (5 ml) ethyl alcohol and hydrogenated for 16 h under a slight positive pressure of hydrogen. The mixture was filtered and concentrated in vacuo to yield 553.2 mg of the carbamic acid as a colorless glass which was used directly for ensuing reaction. TLC: Rf = 0.46, 10% methanol/CH2Cl2.
6. A solution of 102 mg of the resultant compound of a step 5 in 4:1 CH2Cl2/saturated aqueous NaHCO3 was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 65 mg of pnitrobenzenesulfonyl chloride and 51 mg of sodium bicarbonate. The mixture was stirred for 14 h, diluted with CH2Cl2, washed with saturated NaCl, then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by low pressure silica gel chromatography using 20% diethyl ether/CH2Cl2 as eluent to provide 124 mg of the 1-benzyl-3-[isobutyl-(4- nitrobenzenesylfonyl)-amino]-propylcarbamic acid tetrahydrofuran-3(S)-yl] ester as a white solid. TLC: Rf = 0.36, 20% diethyl ether/CH2Cl2, HPLC: Rt = 15.15 min. (1H)-NMR (CDCl3) consist with structure.
7. A solution of 124 mg of the resultant compound of the step 6 in ethyl acetate was treated, at ambient temperature, with 13 mg of 10% palladium on carbon. The mixture was stirred for 14 h under an atmosphere of hydrogen, filtered through a pad of celite filter agent, and concentrated in vacuo. The residue was subjected to preparative HPLC to yield 82 mg of the ((1S,2R)-3-(((4-aminophenyl)sulfonyl)(2-methylpropyl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-, (3S)-tetrahydro-3-furanyl carbamic ester a white solid. TLC: Rf= 0.10, 20% ether/CH2Cl2, HPLC: Rt= 13.16 min. (1H)-NMR (CDCl3) consistent with structure.

brand name

Agenerase (GlaxoSmithKline).

Therapeutic Function

Antiviral

Acquired resistance

Mutations at position 50, 76 and 84 of the protease enzyme gene are associated with significantly reduced susceptibility.

Pharmaceutical Applications

A synthetic compound formulated as the calcium salt of the oral prodrug fosamprenavir.

Pharmacokinetics

Oral absorption: Not known/available
Cmax 700 mg + ritonavir 100 mg:c. 6.08 mg/L
twice daily
Cmin 700 mg + ritonavir 100 mg:c. 2.12 mg/L
twice daily
Plasma half-life: c. 7.7 h
Volume of distribution: c. 430 L
Plasma protein binding: c. 90%
Absorption
Fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate by cellular phosphatases in the gut epithelium as it is absorbed. Absolute bioavailability has not been established. It can be taken without regard to food.
Distribution
It penetrates moderately well into the CNS. The semen:plasma ratio is negligible. It is not known if it is distributed into breast milk.
Metabolism and excretion
It is extensively metabolized by the cytochrome P450 (CYP) 3A4 enzyme system. Two major metabolites have been identified that appear to result from the oxidation of the tetrahydrofuran and aniline moieties. Around 14% of a dose is eliminated in the urine and 75% in feces, <3% as unchanged drug. Metabolites account for >90% of administered drug found in fecal samples. It should be used with caution and at reduced doses in adults with mild or moderate hepatic impairment; it is contraindicated in patients with severe hepatic impairment.

Clinical Use

Treatment of HIV infection (in combination with other antiretroviral drugs)

Side effects

The most common adverse events in patients receiving boosted fosamprenavir were diarrhea, nausea, headache, fatigue, vomiting and rash. Ritonavir-boosted fosamprenavir is associated with a dyslipidemia profile characteristic of those treated with other protease inhibitors boosted with 200 mg of ritonavir.

AMPRENAVIRSupplier

Shanghai Boyle Chemical Co., Ltd.
Email
sales@boylechem.com
J & K SCIENTIFIC LTD.
Tel
010-82848833- ;010-82848833-
Email
jkinfo@jkchemical.com;market6@jkchemical.com
3B Pharmachem (Wuhan) International Co.,Ltd.
Tel
821-50328103-801
Email
3bsc@sina.com
Alabiochem Tech.Co., Ltd.
Tel
0512-58900862;0512-56727736
Email
sales@alabiochem.com;sales@alabiochem.com
Chembest Research Laboratories Limited
Tel
021-20908456-
Email
sales@BioChemBest.com