Influenza neuraminidase inhibitors

Kim CU, Lew W, Wilhams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG, Stevens RC (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119 681-690... 

Kim CU, Lew W, Wilhams MA, Wu H, Zhang L, Chen X, Escarpe PA, Mendel DB, Laver WG, Stevens RC (1998) Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors, J Med Chem 41 2451-2460 Kim CU, Chen X, Mendel DB (1999) Neuraminidase inhibitors as anti-influenza virus agents. Antiviral Chem Chemother 10 141-154... 

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... 

Wang, T. and Wade, R.C. Comparative binding energy (COMBINE) analysis of influenza neuraminidase-inhibitor complexes./. Med. Chem. 2001, 44, 961-971. 

M. Chandler, M. J. Bamford, R. Conroy, B. Lamont, B. Patel, V. K. Patel, I. P. Steeples, R. Storer, N. G. Weir, M. Wright, and C. Williamson, Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D- rrt/fro-L-g/Mco-nonionic acid, J. Chem. Soc. Perkin Trans., 1 (1995) 1173-1180. 

W. Lew, M. A. Williams, D. B. Mendel, P. A. Escarpe, and C. U. Kim, C3-Thia and C3-carba isosteres of a carbocyclic influenza neuraminidase inhibitor, (3R,4R,5R)-4-acetamido-5-amino-3-propoxy-l-cyclohexene-l-carboxylic acid, Bioorg. Med. Chem. Lett., 7 (1997) 1843-1846. 

S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B. Wirz, and U. Zutter, The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu) A challenge for synthesis process research, Chimia, 58 (2004) 621-929. 

G. T. Wang, Y. Chen, S. Wang, R. Gentles, T. Sowin, W. Kati, S. Muchmore, V. Giranda, K. Stewart, H. Sham, D. Kempf, and W. G. Laver, Design, synthesis, and structural analysis of influenza neuraminidase inhibitors containing pyrrolidine cores, J. Med. Chem., 44 (2001) 1192-1201. 

Kim, C. U Lew, W Williams, M. A., Wu, H Zhang, L Chen, X., et al. Structure-Activity Relationship Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors. 

Lew and Kim [66] recently synthesized a sulfide isostere of carbocyclic influenza neuraminidase inhibitor 268, moving from trityl protected aziridine 266, in turn prepared from (-)-quinic acid 159 (Scheme 43). Ring opening of 266 with 1-propanethiol promoted by BF3 etherate, followed by acetylation, gave sulfide 267 which was finally hydrogenated to diamine 268, in a good chemical yield. As the authors expected, mercapto-derivative 268 resulted to be a strong inhibitor of... 

Lew, W. et al. Discovery and Development of GS 4104 (Oseltamivir) an Orally Active Influenza Neuraminidase Inhibitor. 2000 [63a]... 

Karpf, M. et al. New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu). 3.4.4 2001 [135]... 

Lew, W. et al. Carbocyclic Influenza Neuraminidase Inhibitors Possessing a CyCyclic Amine Side Chain Synthesis and Inhibitory Activity. 3.4.4 2000 [143]... 

Mendel DB, Laver WG, Stevens RC. Structure—activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors./. Med. Chem., 1998, 41, 2451-2460. 

These efforts have culminated in the hve-membered carbocyclic compound peramivir 41, which is an orally available influenza neuraminidase inhibitor, obtained by rational design [90]. In a comprehensive study, 41 has been shown to possess neuraminidase activity comparable with both zanamivir 28 and oseltamivir 35 against a number of influenza strains. Furthermore, 41 was found to be very selective for influenza neuraminidase over mammalian, bacterial or other viral neuraminidases. Peramivir 41 is currently undergoing clinical evaluation as an oral treatment for influenza in humans [90b]. 

Several potent influenza neuraminidase inhibitors have been synthesized, and some of them have proven to be effective in treating influenza virus infections in humans. Table 16.5 summarizes the chemical structures and names of these compounds as well as their IC50 values. 

Chemical Structures, Names and IC50 Values of Potent Influenza Neuraminidase Inhibitors... 

Lew, W., Chen, X. and Kim, C.U. (2000) Discovery and development of GS 4104 (oseltamivir) an orally active influenza neuraminidase inhibitor. Current Medicinal Chemistry, 7, 663-672. 

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