Protease inhibitors nelfinavir

Nelfinavir is a nonpeptidic, rationally designed HIV protease inhibitor. Nelfinavir has demonstrated efficacy in both monotherapy and in combination with the reverse transcriptase inhibitors stavudine (d4T) or zivudine + 3TC. The major side effect is mild to moderate diarrhea. 

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). 

Patick AK, Duran M, Cao Y, Pei Z, Keller MR, Peterkin J, Chapman S, Anderson B, Markowitz M.. Genotypic and phenotypic characterization of HIV-1 variants isolated from in vitro selection studies and from patients treated with the protease inhibitor, nelfinavir. Fifth International Workshop on HIV Drug Resistance, Whistler, Canada, 1996 29. 

The most frequent adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea can be dose-limiting but often responds to antidiarrheal medications. Like the other protease inhibitors, nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur as described above. Interactions with antiretroviral agents are summarized in Table 49-4 others may be found in Table 4-2. 

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. 

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. 

S. E. Zook, J. K. Busse, B. C. Borer, A concise synthesis of the HIV-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement, Tetraltedron Lett. 41 (2000) 7017. 

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]... 

Rengan R, Mick R, Pryma D, Rosen MA, Lin LL, Maity AM, et al. A phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB non-small cell Ivmg cancer a report of toxicities and clinical response. J Thorac Oncol... 

Estrogens, furosemide, hydrochlorothiazide, interferon alfa-2b, isotretinoin, propofol, and protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir)... 

Rifampin Daily for 4 months For persons who are contacts of patients with isoniazid-resistant rifampin susceptible TB. In HIV-infected patients, protease inhibitors or NNRTIs generally should not be administered concurrently with rifampin rifabutin can be used as an alternative for patients treated with indinavir, nelfinavir, amprenivir, ritonavir, orefavirenz, and possibly with nevirapine or soft-gel saquinavir5 B (II) B (III)... 

Protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) Rifampin... 

Azalides azithromycin Azoles fluconazole, itraconazole, ketoconazole, and voriconazole Macrolides erythromycin, clarithromycin Protease inhibitors amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir Quinolones ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin. 

In one of these studies, an effort was made to understand the observed dislipidemia and insulin resistance associated with long-term HIV protease inhibitor therapy [25]. Five HIV protease inhibitors (lopinavir, nelfinavir,... 

HIV-1 protease inhibitors Ritonavir Aquinavir Saquinavir Indinavir Nelfinavir... 

HIV protease inhibitors (eg, indinavir, ritonavir, nelfinavir, saquinavir [see Rifapentine-indinavir interaction above]). 

Chemotherapy Cyclophosphamide, erlotlnlb, ifos-famide, paclitaxel, tamoxifen, vinblastine, vincristine HIV protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin... 

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

TC Lamivudine ABC Abacavir d4T Stavudine ddC Zalcitabine ddl Didanosine TDF Tenofovir ZDV Zidovudine, also abbreviated as AZT FTC Emtricitabine NVP Nevirapine DLV Delavirdine EFV Efavirenz RTV, r Ritonavir Pl/r Ritonavir boosted protease inhibitor SQV Saquinavir IDV Indinavir LPV Lopinavir NEV Nelfinavir APV Amprenavir ATV Atazanavir DRV Darunavir... 

Agents within the group of protease inhibitors are nelfinavir (NFV), indinavir (IDV), lopinavir (LPV), saquinavir (SQV), (fos)amprenavir (APV),... 

Nelfinavir (Viracept) is probably the most commonly used protease inhibitor because of its low incidence of serious adverse effects. Its most common side effects are diarrhea and flatulence these may resolve with continued use. In addition to the drugs contraindicated for use with all protease inhibitors, amiodarone, rifampin, and quinidine are contraindicated in patients taking nelfinavir. 

HIV protease is a dimer in which each monomer has an active site containing one or two aspartate residues. Using crystallographic three-dimensional data and molecular modeling studies, drugs have been designed to be transition-state mimetics, aligning at the enzyme active site. Some of the successful protease inhibitors include saquinavir (9.25), ritonavir (9.26), indinavir (9.27), nelfinavir (9.28), and amprenavir (9.29). 

Protease inhibitors amprenavir indinavir sulfate nelfinavir ritonavir... 

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