Tipranavir protease inhibitor

Characterization of an unstable process impurity in the protease inhibitor Tipranavir... 

While using the 0.1 % threshold as a determinant for when an impurity should be isolated to meet regulatory requirements is a good practice, there are other times when it becomes necessary to work with extraneous compounds at still lower levels. During the development of process chemistry for the synthesis of the protease inhibitor Tipranavir several synthetic lots of the drug were discolored, appearing pinkish rather than white as they should. It was determined that a low-level ( 0.1%) highly colored material was responsible for the problem with those lots and a request for the isolation and characterization of that contaminant was received [66]. 

Doyon L, Tremblay S, Bourgon L, Wardrop E, et al. 2005. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptide protease inhibitor tipranavir. Antiviral Res. 68 27-35. 

Figure 2.21 The achiral 4-hydroxypyrone 77 (K, = 10 pM) is structurally related to anticoagulant vitamin K antagonists it was discovered at Parke-Davis as a weakly active lead in a screening for HIV protease inhibitors. Optimization produced the thio ether 78 (K, = 35 nM) and finally CI-1029, 79 (K, = 0.11 nM). In an independent screening, Upjohn discovered that the therapeutically used anticoagulant phenprocoumon 80 (K, = 1 pM) is a weak HIV protease inhibitor. Optimization at Pharmacia and Upjohn produced PNU-96 988, 81 ( ) = 38 nM), and the pico-molar HIV protease inhibitor tipranavir 82 (R,R diastereomer K = 8 pM).

Tipranavir is a protease inhibitor. Tipranavir is a nonpeptide protease inhibitor that prevents formation of mature virions by inhibiting virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells. It is indicated in combination with ritonavir 200 mg for the treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitor. 

Tipranavir The FDA recently granted approval for tipranavir, the first member of a new class of nonpeptide inhibitors of the HlV-1 protease, in combination therapy. Although it also binds to the active site of the HlV-1 protease, tipranavir differs in structure from previously available peptidomimetic protease inhibitors and retains activity against HIV-1 isolates that are resistant to other HIV protease inhibitors. Tipranavir, coadministered with ritonavir, is approved for the treatment of HIV-1-infected adults with evidence of viral replication and who have received multiple treatment regimens or have HlV-1 strains resistant to multiple protease inhibitors. As noted in a black box ... 

Non-Peptidic HIV Protease Inhibitor, Tipranavir as a Drug for the Treatment of HIV... 

One good example of the application of this technology is in the AAA reaction of a racemic vinyl epoxide. The epoxide undergoes a dynamic kinetic asymmetric transformation (DYKAT) by reaction with p-methoxybenzyl alcohol, the standard ligand, and a palladium source. The product is obtained in 69% yield and 98% e.e. After further manipulations a key building block for the nonpeptidic protease inhibitor tipranavir was produced. Coupling of this intermediate with a synthon obtained using a molybdenum-catalyzed DYKAT process led to an advanced intermediate in a total synthesis of tipranavir (Scheme 20.14). ... 

The molybdenum and tungsten complexes catalyze reactions of soft nucleophiles, such as malonates, related 1,3-dicarbonyl compoimds, and nitroalkanes. Azlactones are also soft carbanions, and Trost has shown that complexes formed from molybdenum and the bis(pyridine) ligands catalyze enantioselective and diastereoselective allylation of azlactones with allylic phosphates to form quaternary amino acids (Equation 20.40). In these reactions, the nucleophile adds to the more substituted position of the allylic electrophile, and a stereocenter is formed at both the allyl carbon and the azlactone carbon. One route to the protease inhibitor tipranavir by the molybdenum-catalyzed allylation with 1,3-dicarbonyl compounds was demonstrated by Trost (Equation 20.41), and the Merck process group used related allylation chemistry with Trost s bis(pyridine) ligand to prepare the cyclopentanone precursor to various analogs of tipranavir (Equation 20.42). 

A related molybdenum-based allylation protocol was recently utilized by Trost in a concise total synthesis of the HIV protease inhibitor tipranavir (119, Scheme 14.19) [104], With dipyridine ligand 117, allylated product 118 was readily obtained with excellent yield and enantioselectivity (94%, 96% ee). 

Thaisrivongs S, Strohbach JW (1999) Structure-based discovery of Tipranavir disodium (PNU-140690E) a potent, orally bioavadable, nonpeptidic HIV protease inhibitor. Biopolymers 51 51-58... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Tipranavir is a unique, nonpeptidic protease inhibitor currently in phase 111 clinical trials for HIV treatment. In this compound a phenohc hydroxyl group behaves as a pseudo carboxylic acid group and the chiral hydrogenation step shown in Figure 1.11 gives reasonable enantioselectivity. Benincori et have... 

Tipranavir is a nonpeptide protease inhibitor that is active against HIV-1. Following the binding of tipranavir to the HIV protease, the protease is no longer able to process the gag-pol polyprotein precursors, resulting in the production of immature HIV particles that lack the ability to infect other cells. The resistance to the drug results from site-directed mutagenesis at codons 10, 13, 33, 36,45, 71, 82 and 84 of viral protease. 

King JR, Acosta ER 2006. Tipranavir A novel nonpeptide protease inhibitor of HIV. Clin Phar-macokinet. 45 665-682. 

The various allylic substitution reactions are illustrated in a synthesis of Tipranavir (11), an HIV protease inhibitor. A palladium-catalyzed opening of a vinyl epoxide set the quaternary stereogenic center (Scheme 22.23). A molybdenum-catalyzed allylic nuclophilic displacement was used to access the benzylioc stereogenic center (Scheme 22.24).153... 

Crommentuin KML, Rosing H, Hillebrand MJX et al. (2004) Simultaneous quantification of the new HIV protease inhibitors atzanavir and tipranavir in human plasma by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry. Journal of Chromatography B 804 359-367... 

FLECAINIDE ANTIVIRALS - PROTEASE INHIBITORS Amprenavir, ritonavir and possibly saquinavir and tipranavir with ritonavir t flecainide levels, with risk of ventricular arrhythmias Uncertain possibly inhibition of CYP3A4- and CYP2D6-mediated metabolism of flecainide Manufacturers recommend avoiding co-administration of flecainide with amprenavir, ritonavir and saquinavir... 

RIFABUTIN PROTEASE INHIBITORS t efficacy and t adverse effects of rifabutin Inhibition of CYP3A4-mediated metabolism. Nelfinavir also competitively inhibits 2C19 1 rifabutin dose by at least 50% when given with amprenavir, indinavir or nelfinavir, and by 75% with atazanavir, ritonavir (with or without lopinavir) or tipranavir... 

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