Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a Ki value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.
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PMID:Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. 971

Protease inhibitors are the most well-known type of HIV drug, and five of them are currently approved by the Federal government. This first-generation of protease inhibitors includes Crixivan, Norvir, Fortovase, Viracept, and Agenerase. These drugs, while effective, do not eliminate HIV from the body, nor do they work well for everyone. A second-generation of protease inhibitors is in development, that researchers hope will be easier to take, and better at eliminating HIV. Included in this group are L-756,423, Tipranavir, BMS232632, and ABT-378(r). The benefits and potential drawbacks of each drug are briefly described. People who are considering switching treatments should consult their doctors about the possibility of entering a clinical trial.
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PMID:The younger generation. 1136 65

Updates are provided for new anti-HIV drugs currently in development. ABT-378, Tipranavir, and DMP-450 are among the new protease inhibitors discussed. Drugs from other classes that are discussed include emivirine (Coactinon, formerly MKC-442), FTC (emtricitabine, Coviracil), adefovir (Preveon), and pentafuside (T-20). A small study has found that women using Ritonavir (Norvir) may be at a greater risk for anemia (a decrease in red blood cells), caused by excessive menstrual bleeding or hypermenorrhea. New formulations of Ritonavir and ddI (Didanosine, Videx) are described.
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PMID:New anti-HIV drugs in development. 1136 65

Protease inhibitors block the protease enzyme of HIV-1. When new viral particles break off from an infected cell, protease cuts long protein strands into the parts needed to assemble a mature virus. When protease is blocked, the new viral particles cannot mature. Protease inhibitors being tested in humans include Atazanavir, GW433908, L-756,423, Mozenavir(DMP-450), Tipranavir and more. Several firms are trying to develop a new type of protease inhibitor that will be the more favorable pharmacokinetic and resistance profiles compared with currently available drugs. We cannot expect that every one of the drugs listed in this paper will be successfully developed. However, it is likely that significant clinical advancements can be made with those that are proven to be active and safe for patients in need.
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PMID:[New HIV-1 protease inhibitors in development]. 1196 88

Tipranavir, an important antiviral agent in clinical development for the treatment of HIV, is synthesized in 15 linear steps from readily available starting materials in 25% overall yield by utilizing Pd- and Mo-catalyzed DYKAT reactions to control the quaternary and tertiary stereogenic centers, respectively.
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PMID:Utilization of molybdenum- and palladium-catayzed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers: a concise synthesis of tipranavir. 1245 2

Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.
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PMID:Tipranavir. 1288 70

Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (NPPIs). It is a sulphonamide-containing dihydropyrone, which is highly selective for the HIV protease enzyme and demonstrates potent in vitro activity against wild-type HIV-1 and HIV-2. The IC90 for TPV was 0.1 microM against clinical HIV isolates. Since CYP3A is the major cytochrome P450 isoform for the phase I metabolism of TPV, its exposure is markedly enhanced in the presence of ritonavir (RTV). In one clinical study, using the new self emulsifying drug delivery system (SEDDS) formulation of TPV, plasma concentrations in excess of 20 microM were maintained for 12 hours, allowing for twice-a-day dosing following administration of TPV 300 mg/RTV(r) 200 mg twice a day. The 20 microM target represents 10-fold the IC90 for multiple protease inhibitor (PI)-resistant strains. Both in vitro data and pharmacokinetic results indicate that TPV will be active in vivo against PI-resistant viruses, when given twice a day in combination with low dose RTV. Of 105 HIV viral isolates taken from patients who had been heavily pretreated with PI-based regimens: 90% were fully susceptible to TPV; 8% exhibited intermediate resistance; and 2% were more than 10-fold resistant. In patients who had failed at least two PI-based regimens, only 12.2% of the HIV isolates exhibited four to 10-fold reduced susceptibility to TPV after one year of treatment with a regimen containing the NPPI (Study BI1182.2). A reduction of approximately 1.5 log10 copies/mL in the plasma viral load (pVL) was observed in treatment-naive patients after 15 days of monotherapy with TPV (300 or 1200 mg twice a day) co-administered with RTV (200 mg twice a day) (TPV/r) in a dose-ranging study (Study BI1182.3). The safety and efficacy of TPV (500 or 1250 mg) plus ritonavir (100 mg twice a day) plus two new nucleoside reverse transcriptase inhibitors (NRTIs) was studied in patients failing their first PI-containing regimen (Study BI1182.4). Similar decreases in pVLs (1.44-1.79 log10 copies/mL) were observed after 16 weeks of treatment with either dose of TPV/r. Two doses of TPV/r plus efavirenz (EFV) and a new NRTI have been studied in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients who had failed two or more PI-containing regimens (BI1182.2). Between 50% and 78.9% of patients maintained a pVL < 50 copies/mL for 48 weeks. Clinical studies have shown that TPV/r-associated adverse events are generally gastrointestinal-associated, transient and mild. A phase II study will define the optimal dose of TPV/r for highly treatment-experienced patients. The safety and efficacy of this dose of TPV/r will be evaluated in two phase III studies that will enroll more than 1300 patients worldwide. Tipranavir's robust activity against PI-resistant strains results from its molecular flexibility, which allows it to fit into the active pocket of the protease enzyme in viruses that have become resistant to other PIs.
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PMID:Tipranavir: a protease inhibitor from a new class with distinct antiviral activity. 1456 64

Tipranavir (TPV) is a non-peptidic protease inhibitor belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrones, which exhibits potent and specific activity against HIV type I (HIV-1) and 2 (HIV-2). Clinically effective plasma levels of TPV are achieved by concomitant administration of ritonavir (RTV). Therefore, TPV has been coadministered with RTV in clinical trials. TPV has demonstrated antiviral activity against HIV-1 isolates that are resistant to reverse-transcriptase and selected peptidic protease inhibitors. Therefore, TPV is emerging as one of the newer drugs in the armamentarium against HIV-1 in patients demonstrating multi-drug resistance. TPV administered orally to humans exhibits linear pharmacokinetics at doses of 100 - 2000 mg. Steady-state plasma levels are attained within 7 days of initiating multiple dosing. The half-life of the drug is approximately 6 h at steady-state. The plasma concentration is lower with repeated dosing than predicted from single-dose studies due to induction of the cytochrome p450 3A4 isoform of the liver microsomal enzyme system. Phase II clinical trials have shown that the administration of TPV and RTV in combination is safe and generally well-tolerated in HIV-1-infected adults. Phase III trials are underway to compare the efficacy of this drug versus other antiretroviral regimens. Gastrointestinal toxicity has been described with TPV, the most frequently reported side effects being diarrhoea, nausea, vomiting and abdominal pain. There is no known evidence of teratogenicity or effect on fertility. TPV dosed twice-daily, in the range of 500 - 1250 mg and combined with 100 - 200 mg of RTV has been shown to substantially and durably reduce viral load in HIV-1-infected drug-naive and experienced patients.
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PMID:Tipranavir: a novel non-peptidic protease inhibitor for the treatment of HIV infection. 1458 57

Tipranavir (TPV), a novel nonpeptidic protease inhibitor (NPPI), was administered to treatment-naive HIV-1-infected patients over 14 days in a randomized, multicenter, open-label, parallel-group trial to evaluate the efficacy and tolerability of a self-emulsifying drug delivery system (SEDDS) formulation, in combination with ritonavir (RTV). Of the 31 patients enrolled, 10 were randomized to receive TPV 1200 mg twice daily (TPV 1200), 10 patients received TPV 300 mg + RTV 200 mg twice daily (TPV/r 300/200), and 11 patients received TPV 1200 mg + RTV 200 mg twice daily (TPV/r 1200/200). The median baseline viral load and CD4 cell count were 4.96 log10 copies/mL and 244 cells/mm, respectively. After 14 days, the median decrease in viral load was -0.77 log10 in the TPV 1200 group, -1.43 log10 in the TPV/r 300/200 group, and -1.64 log10 in the TPV/r 1200/200 group. TPV exposure was increased by 24- and 70-fold in the TPV/r 300/200 and 1200/200 groups, respectively, compared with TPV 1200 alone. There were no significant differences across treatment arms with regard to drug-related adverse events. TPV/r appeared to be safe, effective, and well tolerated during 14 days of treatment.
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PMID:A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. 1509 54

Resistance to anti-HIV medications is an ongoing dilemma. A recent study in 16 European countries and Israel found primary drug resistance mutations in 10% of 1,633 people newly diagnosed with HIV disease who had never taken anti-HIV therapy. French clinicians have reported that 78% of viral samples taken between 1997 and 2002 from over 2,000 chronically infected people showed some resistance to at least one antiretroviral drug, and 25% had some resistance to three major drug classes (excluding fusion inhibitors). Similar findings have been reported in the U.S. and Britain. As a significant number of people with HIV find themselves with fewer treatment options, researchers struggle to develop medications that remain effective against genetically varied forms of the virus. Tipranavir, the first in a new category of protease inhibitors (PIs), appears to be such a drug. Studies have shown that tipranavir (formerly known as PNU-140690) durably reduces viral load in some people whose dominant HIV strain is resistant to at least two other PIs. The quality of tipranavir resistance that does develop has also been examined, and the extent of this agent's usefulness in people needing salvage therapy is under investigation.
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PMID:Tipranavir: the first nonpeptidic protease inhibitor. 1510 65


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