Efavirenz

Biological target Efavirenz is a non-nucleoside analogue, direct inhibitor of reverse transcriptase (RT) and thus blocks the transcription of human immunodeficiency virus-1 (HIV-1) viral RNA into the genome of infected cells. The binding at the active site of RT involves unique steric interactions. 

Therapeutic profile The drug is a first choice therapy for patients with HIV-1 infection. 

Synthetic highlights The initial step in the synthetic pathway to efavirenz involves the asymmetric addition of an alkyne anion to the ketone C=0 bond. The generation of chiral Li aggregates elegantly determines the stereoselectivity of the reaction. Scale-up of aUcynylation is promoted by the use of EtaZn as a weak Lewis acid. 

Efavirenz ((5)-l, (- )-6-chloro-4-cyclopropylethynyl-4-triiluoromethyl-1,4-dihydro-2//-3,l-benzoxazin-2-one, Sustiva , Stocrir is widely prescribed for the treatment of the acquired immunodeficiency syndrome (AIDS) and symptomatic HIV-1 infections [1,2]. 

AIDS is caused by two types of viruses, human immunodeficiency viruses HIV-1 and -2, the former being the most prevalent. In 2008, an estimated 33.4 million people worldwide were living with an HIV infection, and around 2 million of these die each year [3]. The AIDS epidemic remains a challenge to worldwide healthcare. In the USA alone, since 1980, 170 billion has been spent on AIDS research, and 

we discovered the first asymmetric nucleophilic addition of acetylides to kehmines. The reaction mechanism was unfortunately not clear during this study but we felt that aggregation of lithium species might play an important role. 

Molecular formula CuHgCIFsNOa Molecular weight 315.68 CAS Registry No 154598-52-4 Merck Index 13,3552 

Sample preparation Condition an Extrasep C18 SPE cartridge (Lida) with 2 mL MeOH and 2 mL water. Dilute 500 p.L serum with 500 (xL water, add to the SPE cartridge, wash with 500 xL water, elute with 1 mL MeOH. Evaporate the eluate to dryness with vortexing under reduced pressure at 40° and reconstitute the residue with 300 p.L MeOH, inject a 10 p.L aliquot. 

Mobile phase Gradient. MeCN 4 mM sulfuric acid from 8 92 to 63 37 over 45 min, maintain at 63 37 for 5 min. 

Lipford, L.C. Determination of serum levels of thirteen human immunodeficiency virus-suppressing drugs by high-performance liquid chromatography, J.Chromatogr.A, 2001, 913, 447-453. 

Sample preparation Mix 1 mL plasma with 200 XL 10 p.g/mL IS in water, add 200 p.L 100 mM NaOH, mix, add 4 mL diethyl ether, shake for 5 min, centrifuge at 2500 rpm for 5 min. Evaporate the organic layer to dryness under a stream of nitrogen, reconstitute the residue with 200 tiL initial mobile phase, inject a 100 iL aliquot. 

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CijH, ClF,NO 168834-43-3) see Efavirenz (2-amino-5-chlorophenyl)phenylmethanone oxime (C17H11CIN2O 18097-52-4) see Chlordiazepoxide... 

CfiHfiClN 106-47-8) see Acetarsol Alprazolam Diazepam Efavirenz Flunitrazepam Flutoprazepam Medazepam Quazepam... 

Ci4H,jC1F,N02 177530-93-7) see Efavirenz (c[5)-5-chIoro-a-(cyclopropylethynyl)-2-[[(4-methoxyphe-nyI)methyl]amino]-a-(trifluoromethyl)benzenemethanol C21HJ9CIF3NO2 173676-60-3) see Efavirenz... 

C4H5F3O2 383-63-1) see Celecoxib Efavirenz Lisinopril ethyl 7,7,7-trifluoroacetoacetate (QH7F30, 372-31-6) see Mefloquine l-ethyl-6,7,8-trilluoro-l,4-dibydro-4-oxa-3-quinoIinecarb-oxylic acid... 

CjHgClO 3282-30-2) see Cefazolin Ceftezole Dexamethasone pivalate Dipivefrine Efavirenz ... 

Tenofovir in its prodrug form tenofovir, disoproxil fumarate (TDF), is indicated in the treatment of HIV infections (AIDS). It is administered as a single oral dose of 300 mg per day. When combined with emtricitabine and efavirenz, TDF has proven to be more efhcacious than the standard combination therapy of combivir (azidothymidine plus lamivudine) and efavirenz (Gallant et al. 2006) and less prone to cause adverse side effects (Pozniak et al. 2006 De Clercq 2007b). 

For the treatment of AIDS, TDF is now available in three commercial preparations, as such (Viread ), in combmation with emtricitabine (Truvada ) and m combination with emtricitabme and efavirenz (Atripla ). The latter represents a three-drugs-in-once combination piU, which has become available for the treatment of AIDS since July 2006. The different milestones mat marked the development and ultimate commercialization of Atripla (m 2006) smce the original identification of adefovir as an antiretroviral agent (m 1986) have been previously reviewed (De Clercq 2006, 2007a-c). 

The first lead compounds for non-nucleoside reverse transcriptase (RT) inhibitors (NNRTl) were discovered about 15 years ago (Pauwels et al. 1990 Merluzzi et al. 1990 Goldman et al. 1991 De Clercq 1993 Riibsamen-Waigmann et al. 1997). Since then they have become an important ingredient of the dmg combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HlV-1) infections. Starting from the HEPT and TIBO derivatives, numerous classes of compounds have been described as NNRTIs. Four compounds (nevirapine, delavirdine, efavirenz and etravirine) have so far been approved for clinical use and several others are the subject of clinical trials (Balzarini 2004 Stellbrink 2007). 

Of the NNRTIs that were first approved, nevirapine and, even more so, efavirenz became cornerstones of HIV therapy because of their potential as a component of HAART (Staszewski et al. 1999). The most commonly used NNRTl drug is efavirenz. In addition, nevirapine was shown to effectively prevent HIV transmission from mother to baby. NNRTIs have proven beneficial when included in drug combination (triple or quadruple) therapy, preferably in the presence of protease inhibitors and NRTIs. 

The reason for the apparently superior antiretroviral activity of raltegravir compared with efavirenz is currently not understood. Several hypotheses have been advanced first, it has been proposed that raltegravir may have superior pharmacokinetic properties that allow it to penetrate more efficiently into HIV sanctuaries such as the gut-associated lymphatic tissue and may thus be more potent at targeting major in vivo-reservoirs of HIV replication (Murray et al. 2007). 

Shulman NS, Bosch RJ, MeUors JW, Albrecht MA, Katzenstein DA (2004) Genetic correlates of efavirenz hypersusceptibility. AIDS 13 1781-1785 Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, Stryker R, Johnson P, Labriola DE, Earina D et al (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341 1865-1873 SteUbrink HJ (2007) Antiviral drugs in the treatment of AIDS what is in the pipeline Eur J Med Res 12 483 95... 

Lalezari JP, DeJesus E, Northfelt DW, Richmond G, Wolfe P, Haubrich R, Henry D, Powderly W, Becker S, Thompson M, Valentine E, Wright D, Carlson M, Riddler S, Haas FF, DeMasi R, Sista PR, Salgo M, Delehanty J (2003a) A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in nonnucleoside reverse transcriptase inhibitor-naive HIV-infected adults. Antivir Ther 8 279-287... 

Podzamczer D, Ferrer E, GateU JM, Niubo J, Dalmau D, Leon A, Knobel H, Polo C, Iniguez D, Ruiz I (2005) Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther 10 171-177... 

Zidovudine Didanosine Stavudine Lamivudine Abacavir Tenofovir Emtricitabine Nevirapine Efavirenz TMC125 Saquinavir Indinavir Lopinavir Fosamprenavir Atazanavir Tipranavir Darunavir Raltegravir Elvitegravir Enluvirtide Maraviroc Vicriviroc Bevirimat... 

Tenofovir + Emtricitabine Zidovudine + Lamivudine Abacavir + Lamivudine Efavirenz or Nevirapine Lopinavir/r or Atazanavir/r or Eosamprenavir/r or Saquinavir/r... 

Makela and colleagues described the occurrence of a probable recurrent GBS six weeks after initiation of HAART and after a striking increase in CD4 cell count in an HfV-infected individual (Makela et al. 2002). Piliero and colleagues described an HIV-infected patient with AIDS who developed GBS, 26 days after initiation of a 6-drug HAART regimen, which had led to an impressive immune reconstitution (a rise in CD4 cell count from 31 to 602 cells/pL) (Piliero et al. 2003). Puthanakit and colleagues identified a child who developed GBS, 3 weeks after initiation of efavirenz-based HAART in a cohort of HIV-infected Thai children (Puthanakit et al. 2006). 

Conversely buprenorphine metabolism could by increased by carbamazepine, phenytoin, St. John s wort, efavirenz, and nevirapine, or any other CYP3A4 inducer the effects may be less than expected may need to increase buprenorphine dose. 

This HIV drug is a CYP3A4 inducer efavirenz decreases... 

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