Protease inhibitors, for treatment

Yoshinaka, Y Kato, I. Igawa, Y Adachi, S. Virus protease inhibitors for treatment of vims infectious diseases. Jpn. Kokai Tokkyo Koho JP 03291227, 1991 Chem. Abstr. 1992,117, 20488. 

HIV infection In combination with other antiretroviral agents (such as nonnucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. 

Kakuda TN, Struble KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency virus infection. Am J Health Syst Pharm 1998 55 233-54. 

The silanediol 21 has been prepared for use as a potential protease inhibitor by treatment of arylsilane 22 with CF3SO3H. This is a convenient method for the preparation of silyl triflates (which are readily hydrolysable, see below) but in this case it is thought that the amide carbonyl intercepts the protonated species 23 (loss of the t-Bu ester group also occurring) to give the spirocyclic silyl ether 24, which is then hydrolysed to give the diol, (Scheme 5)94. 

In UK and US guidelines, the combination of didanosine with emtricitab-ine is currently a recommended alternative dual NRTI option for use with an NNRTI or a protease inhibitor, for the treatment of HIV-infection in... 

Lamivudine is cleared predominantly from the body by the kidneys using the organic cationic transport system. Didanosine is not cleared by this mechanism and so is unlikely to interact with lamivudine by this mechanism. Didanosine does not affect the intracellular activation of lamivudine in vitro. In UK and US guidelines, the combination of didanosine with lamivudine is currently a recommended alternative dual NRTI option for use with an NNRTI or a protease inhibitor, for the treatment of HIV-infection in treatment naive patients. 

So far, five different protease inhibitors have been approved by the FDA for the treatment of HIV infection [3, 4]. Clinical trials in which protease inhibitors were evaluated in monotherapy demonstrated the potency of this class of inhibitors (decrease in HIV RNA levels, increase in CD4 cell counts). Treatment regimens were subsequently broadened to include reverse transcriptase inhibitors in combination with protease inhibitors. The result of these clinical trials has led to a list of guidelines with recommendations for the optimal treatment options. Prolonged control of the infection with combination therapy (highly active antiretroviral therapy, HAART ) could be shown. 

Saquinavir was the fust HIV protease inhibitor to obtain FDA approval in 1995 for the treatment of HIV infection... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

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