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Tipranavir HIV protease inhibitor

Catalog No.A3876
Size Price Stock
5mg
$580.00
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10mg
$980.00
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Sample solution is provided at 25 µL, 10mM.

Quality Control

Quality Control & MSDS

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Chemical structure

Tipranavir

Protocol

Kinase experiment [1]:

Inhibitory activities

The inhibition constant (Ki) for tipranavir (TPV) was determined by measuring the change in fluorescence associated with the cleavage of the fluorogenic substrate Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg. Enzymatic assays were performed in 10 mM sodium acetate buffer, pH 5.0, with 40 μM substrate and 1 to 400 nM protease at 25℃. The inhibitor concentration varied between 2 nM and 1 μM, depending on the type of inhibitor and mutant used. Several aliquots at different concentrations were prepared by diluting the stock solution (15 mM) in 100% DMSO. The final concentration of DMSO was 2% (vol/vol) in all reaction mixtures. Fluorescence was measured on a CytoFluor fluorescence multiwell plate reader with an excitation wavelength of 360 nm and an emission wavelength of 508 nm. Hydrolysis rates were obtained from the initial portion of the data, where at least 80% of the substrate remained nonhydrolyzed.

Human experiment [2]:

Patients

HIV-1-infected patients.

Dosage form

500 mg twice daily or 1000 mg twice daily administered with ritonavir (100 mg twice daily); 80 weeks.

Applications

TPV induces a consistent and durable reduction in viral load and increases the amount of CD4+ cells.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Muzammil S, Armstrong AA, Kang LW, et al. Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J Virol, 2007, 81(10): 5144-5154.

[2]. Markowitz M, Slater LN, Schwartz R, et al. Long-term efficacy and safety of tipranavir boosted with ritonavir in HIV-1-infected patients failing multiple protease inhibitor regimens: 80-week data from a phase 2 study. J Acquir Immune Defic Syndr, 2007, 45(4): 401-410.

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Chemical Properties

Cas No. 174484-41-4 SDF Download SDF
Synonyms Aptivus,Tipranavir
Chemical Name N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide
Canonical SMILES CCCC1(CC(=C(C(=O)O1)C(CC)C2=CC(=CC=C2)NS(=O)(=O)C3=NC=C(C=C3)C(F)(F)F)O)CCC4=CC=CC=C4
Formula C31H33F3N2O5S M.Wt 602.66
Solubility Soluble in DMSO Storage Store at -20°C
Physical Appearance A crystalline solid Shipping Condition Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Background

Tipranavir is a potent HIV protease inhibitor, which has been proven effective in inhibiting the HIV protease with a Ki value of 8 pM and showing an IC90 value of 100 nM [1].
It is believed that tipranavir can block the replication of numbers of viruses resistant to the current range of protease inhibitor. And the major amino acid substitutions of HIV-1 protease were identified to be associated with tipranavir sensitivity and resistance .[2]
As a highly potent HIV protease inhibitor , tipranavir inhibited HIV-2 protease with high potency (Ki < 1 nM) and was also effective against V82A and V82F/I84V mutants (Ki 3.0 and 0.25 nM, respectively). High Ki values against other aspartyl proteases such as human pepsin, cathepsins D and E illustrated the selectivity for HIV protease. An investigation of the effect of protein binding on antiviral activity was performed in HIV-1IIIB infected cells in a medium of 10% fetal bovine serum and 75% human plasma, where above 99% of the inhibitor is protein bound and an IC90 value of 1.4 µM was observed [1] . Additionally, a study of antiviral activities of tipranavir was operated with 134 clinical isolates in vitro, which showed the attractive properties of broadly protease inhibitor resistant HIV clinical samples [2].
In a mouse model with 5 mg/kg tipranavir dosing, as a result, CLtot was 0.17 ± 0.10 L/h/kg, Vss was 0.51 ± 0.14 L/kg, and t1/2 was 5.4 ±0. 3h. And following 10 mg/kg oral dosing in rats, got the result of F was 30% compared to 5 mg/kg tipranavir dosing [1]. After being proved an effective therapeutic agent for treatment of AIDS.  An evaluating of the long-term (up to week 292) safety, efficacy and tolerability of ritonavir-boosted tipranavir was carried out in HIV-1-infected pediatric patients. The result of the evaluating indicated that the pediatric patients do well with regard to safety, tolerability and virologic efficacy when they are stable on a tipranavir-based regimen [3].
References:
1.Turner SR, Strohbach JW, Tommasi RA , et al.Tipranavir (PNU-140690):  A Potent, Orally Bioavailable Nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class. Journal of Medicinal  Chemistry, 1998,41 (18), 3467-3476.
2.Larder BA , Hertogs  K , Bloor S ,et al. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS, 14 (13), 1943-1948.
3.Salazar JC, Cahn P, Della Negra M, et al. Efficacy and safety of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents: 5 years of experience. The Pediatric Infectious Disease Journal, 2014, 33 (4), 396-400.