Reverse transcriptase inhibitors analogues

The 2, 3 -dideoxynucleoside (ddN) analogues (Fig. 3) encompass a vast group of compounds that have been found active against HIV and HBV, although they have been primarily pursued for the treatment of HIV infections (AIDS). They are targeted at the HIV-associated reverse transcriptase (RT) and therefore also referred to as nucleoside reverse transcriptase inhibitors (NRTIs). They have to be distinguished from the nucleotide reverse transcriptase inhibitors (NtRTIs) such as adefovir (PMEA) and tenofovir (PMPA) (see above) which, like the NRTIs, act as chain... 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

O N +, HSO4- Inhibitor of reverse transcriptase (Ellipticin analogue) 1996BML2831... 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

A potentially fatal hypersensitivity, or allergic reaction, has been associated with the use of aba-cavir, a nucleoside analogue reverse transcriptase inhibitors recently approved for treatment of AIDS in adults and children, in at least 5% of patients. Symptoms of this reaction may include skin rash, fever, nausea, abdominal pain and severe tiredness. 

L D. Lamivudine, a cytosine analogue, is a nucleoside reverse transcriptase inhibitor that acts as a competitive inhibitor of reverse transcriptase. Efavirenz is a nonnucleoside reverse transcriptase inhibitor it acts by binding to a site adjacent to the enzyme s active site. Neither drug exhibits significant activity against HIV protease. 

An efficient synthesis of the l-aUyl-6-(l, 2, 3 -triazolyl) analogue 170 of 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (KEPT), an anti-human immunodeficiency virus (HIV) reverse transcriptase inhibitor, was reported using an intermolecular 1,3-dipolar cycloaddition of the azide 169 with acetylenes (35) (Scheme 9.35). Azidouracil (169), when refluxed with an acetylene in equimolar proportions in toluene, gave the corresponding triazoles (170) in excellent yield. 

Gallant JE, Gerondelis PZ, Wainberg MA, Shulman NS, et al. 2003. Nucleoside and nucleotide analogue reverse transcriptase inhibitors A clinical review of antiretroviral resistance. Antivir Ther. 8 489-506. 

Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin. 

Nucleoside analogue reverse transcriptase inhibitors (NRTIs)... 

Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999 354 1112-5. 

The constrained nucleosides are of interest as leads for small-molecule therapeutics. For example, the (3-2 -0,3 -C-oxetane analogues of the antiviral 3 -azido-3 -deoxythymidine (AZT), which exist predominantly in the E-like conformation (see, for example, Equation 55), were investigated for inhibition of human immunodeficiency virus 1 (HIV-1). Neither the modified nucleosides nor their 5 -monophosphate analogues inhibit HIV-1, supporting a hypothesis that reverse transcriptase inhibitors must have conformational freedom <2001JOC4878, 2002J(P1)1655>. 

Barreca et al screened for non-nucleoside reverse transcriptase inhibitors of HIV-1 by searching the Derwent World Drug Index (WDI) and the Chemicals Available for Purchase (CAP) databases with a Catalyst model generated by LigandScout. A Fit value cutoff of 3.0 and Lipinski filters, followed by docking, led to the selection of three compounds, two of which were commercially available. A search for available close analogues of all three compounds finally led to the purchase of six compounds, of which five were shown to be active. 

Lamivudine is a nucleoside analogue, which acts as a reverse transcriptase inhibitor of HBV-DNA polymerase and causes a break in the molecular chain through its competitive integration in the DNA. Lamivudine is administered orally and well resorbed. The half-life is 5-7 hours it is eliminated unchanged via the kidneys. Therefore, the dose must be adjusted to the patient s creatinine clearance. 

Nucleoside analogue reverse transcriptase inhibitors (NRTIs), Nonnucleoside analogue reverse transcriptase inhibitors (NNRTls), Protease inhibitors (Pis),... 

Nucleoside analogue reverse transcriptase inhibitors are drugs of diverse chemical structure that act by non-competitive inhibition of HIV-1 reverse transcriptase. 

Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated the PENTA 5 randomised trial. Lancet 2002 359(9308) 733-40. 

Adefovir is an adenine analogue reverse transcriptase inhibitor. While it has activity against both HIV and hepatitis B, its use in HIV infection is limited by nephrotoxicity due to the high doses needed (1). The dose used for treatment of hepatitis B is about one-tenth that needed to treat HIV infection, so patients with hepatitis B must have co-infection with HIV ruled out before treatment is started. 

Lamivudine (3TC) is a nucleoside analogue reverse transcriptase inhibitor that has been widely used against HIV infection which also has antiviral effects against hepatitis B (1). 

Lopinavir and ritonavir are nucleoside analogue reverse transcriptase inhibitors that are used in combination in the treatment of AIDS. 

The non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) include delavirdine, efavirenz, and nevirapine (all rINNs). The pharmaceutical chemistry and uses of the first- and second-generation NNRTIs have been reviewed (1). 

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

---