Human immunodeficiency virus nelfinavir

In addition, new some epoxide hydrolases have also shown a great utility for the desymmetrization of meso-epoxides. An interesting example is the synthesis of nelfinavir-the active pharmaceutical ingredient (API) of the anti-human immunodeficiency virus drug Viracept-where the (R,R)-diol obtained by opening the meso-epoxide is a suitable starting material. Scheme 10.6 shows a synthetic route to nehinavir [14]. 

Nelfinavir is indicated for the treatment of human immunodeficiency virus (HIV) infection when antiretroviral therapy is warranted. At present, there are no results from controlled trials evaluating the effect of therapy with nelfinavir on clinical progression of HIV infection, such as survival or the incidence of opportunistic infections. 

An unusual example of oxazoline formation is illustrated in the following example in which the hydroxyl moiety is masked as a tetrahydrofuran ring. Depending on reaction conditions, regioselective ring closure to one of the two oxazolines can be realized. Thus, addition of methanesulfonyl chloride to a mixture of substrate and EtsN resulted in the expected oxazoline 46. On the other hand, addition of < 1 equiv of triethylamine to a mixture of substrate and methanesulfonyl chloride, followed by acid catalysis produced oxazoline 47. Intermediate 47, obtained in 72% overall yield from 45, was susequently converted to the human immunodeficiency virus (HlV)-protease inhibitor Nelfinavir 48 (Scheme 8.18). 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Markowitz M, Conant M, Hurley A, Schluger R, Duran M, Peterkin J, Chapman S, Patick A, Hendricks A, Yuen GJ, Hoskins W, Clendeninn N, Ho DD. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-l protease, to treat HIV infection. J Infect Dis 1998 177(6) 1533-40. 

Moyle GJ, Youle M, Higgs C, Monaghan J, Prince W, Chapman S, Clendeninn N, Nelson MR. Safety, pharmacokinetics, and antiretroviral activity of the potent, specific human immunodeficiency virus protease inhibitor nelfinavir results of a phase I/II trial and extended follow-up in patients infected with human immunodeficiency virus. J CUn Pharmacol 1998 38(8) 736-43. 

Honda M, Yasuoka A, Aoki M, Oka S. A generalized seizure following initiation of nelfinavir in a patient with human immunodeficiency virus type 1 infection, suspected due to interaction between nelfinavir and phenytoin. Intern Med 1999 38(3) 302-3. 

Krogstad P, Lee S, Johnson G, Stanley K, McNamara J, Moye J, Jackson JB, Aguayo R, Dieudonne A, Khoury M, Mendez H, Nachman S, Wiznia A, Ballow A, Aweeka F, Rosenblatt HM, Perdue L, Frasia A, Jeremy R, Anderson M, Japour A, Fields C, Farnsworth A, Lewis R, Schnittman S, Gigliotti M, Maldonaldo S, Lane B, Hernandez JE, et al Pediatric AIDS Clinical Trials Group 377 Study Team. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis 2002 34(7) 991-1001. 

Lillibridge JH, Liang BH, Kerr BM, et al. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Disp. 1998 26 609-616. 

Successful treatment of human immunodeficiency virus (HIV-1) infection has been achieved through successful implementation of highly active antiretroviral therapy, frequently referred to as HAART. This involves simultaneous administration of both nucleoside and nonnucleoside reverse transcriptase inhibitors and one or more protease inliibitors. The common nucleoside reverse transcriptase inhibitors are the thymidine analogs didanosine (ddl), lamivudine (3TC), and zalcitabine (ddC) and the non-thymidine analogs abacavir (Ziazen), stavudine (d4T), and zidovudine (AZT). The nonnucleoside reverse transcriptase inhibitors include delavirdine, efavirenz, and nevirapine. The protease inhibitors include indinavir, nelfinavir, ritonavir, and saquinavir. Response to therapy is monitored by quantification of HIV-RNA copies (viral load) and CD-4+ T-lymphocyte count. Successful therapy is indicated when viral load is reduced to <50 copies/mL and CD-4+ count >500 per mL. 

Jackson, K.A., Rosenbaum, S.E., Kerr, B.M., Pithavala, Y.K., Yuen, G. and Dudley, M.N. A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a Phase III clinical trial. Antimicrobial Agents and Chemotherapy 2000 44 1832-1837. 

Nelflnavir mesylate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme required to form functional proteins in HIV-infected cells. It is indicated in the treatment or HIV infection in combination with other antiretroviral agents. Nelflnavir is a non-peptidic protease inhibitor that is active against both HIV-1 and HIV-2 and is formulated as the mesylate salt of a basic amine. The mean IC95 for HTV-1 in various in vitro assays is 59 nM. Like most drugs in this class, nelfinavir was a product of rational drug design. 

Riddler SA, Havlir D, Squires KE, Kerr B, Lewis RH, YehK, Hawe Wynne L, Zhong L, Peng Y, Deutsch P, Saah A, Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults safety, pharmacokinetics, and antiretroviral activity, Antimicrob Agents Chemother (2002) 46, 3877-82. 

Simon, VA. Thiam, M.D. Lipford, L.C. Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance hquid chromatography, J.ChromatogrA, 2001,913,447-453. [zalcitabine lamivudine stavudine didanosine zidovudine nevirapine abacavir indinavir delavirdine nelfinavir saquinavir ritonavir efavirenz]... 

Zhang, K.E. Wu, E. Patick, A.K. Kerr, B. Zorbas, M. Lankford, A. Kobayashi, T. Maeda, Y. Shetty, B. Webber, S. Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans Structural identification, levels in plasma, and antiviral activities, Antimicrob.Agents Chemother., 2001,45, 1086-1093. [LC-MS reserpine is internal standard LOQ 20 ng/mL]... 

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