Non-nucleoside inhibitor

Non-nucleoside inhibitors JTK003 B1LB1941 P495A/L/S/T, P496A/S, V499A... 

As for HIV, the selection of HCV drug resistant variants can be accompanied by a decrease in RC. For HCV protease inhibitor resistant variants, the level of resistance seems to be inversely related to viral fitness (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). There is some evidence that viral RC can be restored by the selection of compensatory mutations within the protease gene (Sarrazin et al. 2007 Tong et al. 2006 Yi et al. 2006). However, further research is warranted to investigate to what extent viral fitness can be restored and by which mutations. Also for the nucleoside and non-nucleoside inhibitors, the selection of resistance results in a fitness defect. It remains to be investigated whether or not compensatory mutations can be selected. 

Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefebvre S, Thauvette L, Gauthier J, Goulet S, Poupait MA, Beaulieu PL (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase, J Biol Chem 280 39260-39267... 

R1626 (prodrug of R1479) Non-nucleoside inhibitor Roche Phase 2... 

Williams TM, Ciccarone TM, MacTough SC, Rooney CS, Balani SK, Con-dra JH, Emini EA, Goldman ME, Greenlee WJ, Kauffman LR, O Brien JA, Sardana VV, Schleif WA, Theoharides AD, Anderson PS. 5-Chloro-3-(phe-nylsulfonyl)indole-2-carboxamide a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J Med Chem 1993 36 1291-1294. 

Saag MS, Emini EA, Laskin OL, Douglas J, Lapidus WI, Schleif WA, Whitley RJ, Hildebrand C, Byrnes VW, Kappes JC, Anderson KW, Massari FE, Shaw GM, the L-697,661 Working Group. A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 1993 329 1065-1072. 

Mellors JW, Dutschman GE, Im G-J, Tramontano E, Winkler SR, Cheng Y-C. In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 1992 41 446-451. 

Jorgensen, W. L. Ruiz-Caro, J. Tirado-Rives, J. Basavapathruni, A. Anderson, K. S. Hamilton, A. D. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2006,16, 663-667... 

The non-nucleoside inhibitors of reverse transcriptase (nevirapine, dela-virdine, efavirenz) are not phosphory-lated. They bind to the enzyme with high selectivity and thus prevent it from adopting the active conformatioa Inhibition is noncompetitive. 

ZD-9331 is a non-nucleosidic inhibitor of thymidylate synthase. It is also an antifolate, in which the quinazoline moiety replaces the pteridine entity, structurally close to methylene tetrahydrofolate (i.e., the second substrate of thymidylate synthase). Moreover, replacement of the acid function of glutamic acid by a tetrazole renders polyglutamination impossible. Consequently, ZD-9331 is active on tumors that are resistant to the usual antifolates. ... 

Esnouf R, Ren J, Ross R, Jones Y, Stammers D, Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nature Struct Biol 1995 2 303-308. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

The three part so-called cocktail used to treat HIV positive patients typically comprise a proteinase inhibitor, such as those discussed in Chapter 1 a nucleoside-based reverse transcriptase inhibitor, such as those in Chapter 6, and a non-nucleoside inhibitor of reverse transcriptase (NNRTI). Most of the compounds in the first two classes share a good many structural features with other agents in the class. Chemical structures of the various NNRTIs on the other hand have little in common. Capravirine (103), is notable in the fact that it fails to include any of the fused ring systems that provide the nucleus for other compounds in this class. Chlorination of 3-methylbutyraldehyde (94) provides one of the components for building the imidazole ring. For bookkeeping purposes, the condensation of 94 with 0-benzyl glyoxal and ammonia can be... 

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