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Non-Nucleoside Reverse Transcriptase Inhibitors: the NNRTI Boom

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Non-Nucleoside Reverse Transcriptase Inhibitors: the NNRTI Boom Antiviral Chemistry & Chemotherapy 10:285–314 Review Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom Ole S Pedersen and Erik B Pedersen* Department of Chemistry, University of Southern Denmark, Odense University, DK-5230 Odense M, Denmark *Corresponding author: Tel: +45 6550 2555; Fax: +45 6615 8780; E-mail: [email protected] Non-nucleoside reverse transcriptase inhibitors approved NNRTI drugs and focuses on the recent (NNRTIs) are promising drugs for the treatment of efforts being made to produce second genera- HIV when used in combination with other anti- tion inhibitors that circumvent this resistance HIV drugs such as nucleoside reverse transcriptase problem. (RT) inhibitors and protease inhibitors. The first generation of NNRTIs have, however, suffered Keywords: HIV-1; non-nucleoside reverse from the rapid development of resistance. This transcriptase inhibitors; HEPT; nevirapine; review discusses the properties of the FDA- delavirdine; efavirenz; trovirdine Introduction The HIV epidemic is still a major concern. Virtually every interest in NNRTIs we intend to review this class of com- country in the world has seen new infections in 1998, and pounds, especially the second generation of NNRTIs, using the epidemic is out of control in many places according to a chemical approach. This review will focus on the recent the World Health Organization (WHO) and the Joint and most interesting published results. The NNRTIs syn- United Nations Programme on HIV/AIDS (UNAIDS). thesized before 1996 are covered by reviews by Artico The introduction of highly active antiretroviral therapy (1996) and Tucker et al. (1996). A review focusing on the (HAART), which has been used mainly in North America role of NNRTIs in the therapy of HIV-1 infections has and Western Europe, has reduced the number of deaths been published by De Clercq (1998a). caused by AIDS. However, because new infections continue to occur and infected people are kept alive with HAART Non-nucleoside reverse transcriptase and other combinations of anti-HIV drugs, the number of inhibitors people living with HIV has increased in North America and Western Europe. Combinations of anti-HIV drugs NNRTIs are bound in a hydrophobic pocket proximal to often contain a non-nucleoside reverse transcriptase (RT) the catalytic site of RT in HIV-1 (Tantillo et al.,1994). X- inhibitor (NNRTI), a nucleoside RT inhibitor (NRTI) and ray crystallographic studies of NNRTIs in complex with a protease inhibitor. This review will concentrate on the RT (Ren et al., 1995; Ding et al., 1995) have shown that the NNRTIs, of which the first, nevirapine (Viramune, NNRTIs maintain a very similar conformational ‘butterfly- Boehringer Ingelheim), was approved as a drug for the like’ shape and appear to function as π-electron donors to treatment of HIV-1 infection by the US Food and Drug aromatic side-chain residues surrounding the binding Administration (FDA) in 1996. Nevirapine was followed pocket (Kroeger et al., 1995; De Clercq, 1998b). by delavirdine mesylate (Rescriptor, Pharmacia & Upjohn) The major problem in the development of new and efavirenz (Sustiva, DuPont), approved for the treat- NNRTIs is the rapid emergence of resistant strains of ment of HIV-1 infection by the FDA in 1997 and 1998, HIV-1 in cell culture and patients. In patients receiving respectively. A further three compounds, MKC-442 monotherapy with nevirapine, drug resistance developed (Triangle Pharmaceuticals), Calanolide A (Sarawak rapidly owing to mutations in the RT; particularly signifi- MediChem Pharmaceuticals) and AG 1549 (Agouron cant is the Y181C mutation (Cywin et al.,1998). Cross- Pharmaceuticals) are in clinical trials according to the resistance is also a contributing factor and Pharmaceutical Research and Manufacturers of America pyridinone-resistant strains containing the Y181C, K103N (PhRMA) 1998 survey report. Because of the increasing or both mutations (Nunberg et al., 1991) have been found ©1999 International Medical Press 0956-3202/99/$17.00 285 OS Pedersen & EB Pedersen Figure 1. The structure of nevirapine mutant strains of HIV-1 have to be considered in the devel- opment of new NNRTI drug candidates. These aspects O include metabolic stability, clearance rates, the ability to H3C 5 H N cross the blood–brain barrier and protein binding. Protein binding is a complex issue; a high protein binding could 4 reduce the metabolism of the drug, the clearance rates and 11 maintain high concentration of the drug in the blood. 2 N N N However, too strong protein binding may reduce the con- 10 1 centration of the free drug available for inhibitory action. Some of the currently most interesting subclasses of NNRTIs are described below. Tables showing the antiviral activity and activity against purified RT are presented. The to confer resistance to both TIBO R82150 (Pauwels et al., presentation of each drug begins with the subclass with an 1990) and nevirapine (Merluzzi et al., 1990). It has been FDA approved drug, followed by a subclass with a drug in shown that NNRTIs rapidly select for resistant mutant clinical trials according to the PhRMA 1998 survey report, HIV-1 strains when selection pressure is applied by drugs and ends with a description of some additional characteris- in vitro (Kleim et al., 1995; Nunberg et al., 1991) or in tic subclasses. monotherapy (Cywin et al., 1998; Miller et al., 1998). Cross-resistance has been observed between many Nevirapine NNRTIs in development (Miller et al., 1998). Mutations Nevirapine (Viramune; Boehringer Ingelheim) (Figure 1) commonly selected for by NNRTIs occur at amino acid was approved for the treatment of HIV in combination positions 98 to 108, 179 to 190 and 230 to 236 (Miller et with nucleoside analogues in 1996 in the USA, and in 1998 al., 1998). Cross-resistance is one of the obstacles that has in the European Union. to be overcome for the next generation of NNRTIs, new Nevirapine has a good potency against wild-type RT, drugs that have a resistance profile that differs from the with a 50% inhibitory concentration of 84 nM (Hargrave resistance profile of the already known drugs. et al.,1991), good metabolic stability, good bioavailability Many aspects beside selectivity and activity against (Cywin et al. 1998) and crosses the blood–brain barrier eas- Table 1. The activity of some nevirapine analogues against wild-type RT and two mutant strains of HIV-1 RT O H3C N N N N R1 R2 IC50 (µM) HIV-1 RT* Compound R1 R2 WT† Y181C Y188L Reference 1ClEt0.08 0.21 ND‡Proudfoot et al. (1995a) 2 N-pyrrolyl Et 0.09 0.21 ND Proudfoot et al. (1995a) 3 2-furanyl Et 0.11 0.16 ND Proudfoot et al. (1995a) 4 3-furanyl Et 0.04 0.11 ND Proudfoot et al. (1995a) 5 2-pyrrolyl Et 0.07 0.07 ND Proudfoot et al. (1995a) 6 3-pyrrolyl Et 0.033 0.050 ND Kelly et al. (1997) 7 3-pyrrolyl c-Pr 0.05 0.06 ND Proudfoot et al. (1995a) 8 4-pyrazolyl Et 0.02 0.06 ND Proudfoot et al. (1995a) 9 4-pyrazolyl c-Pr 0.06 0.05 ND Proudfoot et al. (1995a) 10 4-NH2-phenyl Et 0.04 0.12 ND Proudfoot et al. (1995a) 11 indol-3-yl Et 0.028 0.028 0.090 Kelly et al. (1997) 12 5-azaindol-3-yl Et 0.044 0.098 0.384 Kelly et al. (1997) *Inhibitor concentration to give 50% inhibition of incorporation of [3H]dGTP into a [(poly)rC•(oligo)dG] template. †Wild-type HIV-1RT. ‡ND, Not determined. 286 ©1999 International Medical Press The NNRTI boom Table 2. The activity of some nevirapine analogues against wild-type RT and two mutant strains of HIV-1 RT H3C O N R2 N N N R1 IC50 (µM) HIV-1 RT* Compound R1 R2 WT† Y181C Y188L Reference 13 Cl (3-ureidophenyl)ethyl 0.06 0.08 0.23 Klunder et al. (1998) 14 Cl (3-anilinyl)ethyl 0.12 0.23 0.25 Klunder et al. (1998) 15 Cl (4-(2-aminopyridyl))ethyl 0.02 0.07 0.16 Klunder et al. (1998) 16 F (4-pyridyl)ethyl 0.05 0.08 0.25 Klunder et al. (1998) 17 I (4-pyridyl)ethyl 0.09 0.18 0.43 Klunder et al. (1998) 18 Cl (4-pyridyl)ethyl 0.08 0.12 1.85 Klunder et al. (1998) 19 Cl (phenylthio)methyl 0.02 0.01 0.03 Cywin et al. (1998) 20 Cl (phenyloxy)methyl 0.11 0.06 0.64 Cywin et al. (1998) 21 Cl (2-methyl-4-pyridinyl-oxy)methyl 0.03 0.03 0.23 Cywin et al. (1998) 22 Cl phenylethyl 0.05 0.15 0.96 Cywin et al. (1998) 23 Cl (3-(aminocarbonyl)phenyloxy)methyl 0.13 0.28 0.34 Cywin et al. (1998) 24 Cl (3-aminophenyloxy)methyl 0.05 0.10 0.37 Cywin et al. (1998) *Inhibitor concentration to give 50% inhibition of incorporation of [3H]dGTP into a [(poly)rC•(oligo)dG] template. †Wild-type HIV-1 RT. ily (Glynn & Yazdanian, 1998). Like all current NNRTIs, HIV activity against both wild-type RT and a broad spec- nevirapine selects for mutations in the RT, the most com- trum of mutant RTs (Klunder et al.,1998). The aim in the mon resistant strain of HIV-1 being characterized by the synthesis of these derivatives has been to achieve multiple Y181C mutation. Mutations appear rapidly in response to interaction points with the enzyme or to achieve interac- treatment with NNRTIs administered as monotherapy, tion between the compound and some more conserved and the focus of researchers working with nevirapine ana- residues of RT. Some of these residues include the catalyt- logues has been to develop drug candidates that retain ic aspartic acid residues, Asp-110, Asp-185 and Asp-186.
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