Tipranavir (Synonyms: PNU-140690)

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.