Carbocycle influenza neuraminidase inhibitor

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... 

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. 

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. 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. 

The vicinal diol 216, prepared in 10 steps from quinic acid, was elaborated into V-alkylated 2-epi-valienamines 217 in variable (16-98%) yield by reaction with Viehe s salt followed by Pd(0)-catalysed coupling with a range of primary e.g. R = H = Et, Bu, Hept, Oct, cyclohexyl, Bn) and secondary amines e.g. R = R = Bu, cyclohexyl, Pr). Carbocyclic influenza neuraminidase inhibitors 219 (n = 3-8) with a cyclic amine side-chain have also been prepared via Pd(0)-catalysed coupling of acetate 218 with the corresponding cyclic amines. The use of pentafunctional quinic acid as a polyoxygenated scaffold for combinatorial synthesis has also been described. ... 

R.C. (1998) Structure-activity relationship studies of novel carbocyclic 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... 

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]. 

Prompted by the success achieved with simple carbocyclic compounds (e.g., 35), which are potent inhibitors of influenza neuraminidase, several other Neu5Ac2en mimetics of this kind were studied. The isomeric carbocyclic derivatives 37 and 38 are selective for influenza A sialidase, but only 38 showed signihcant inhibition (IC50 = 2 X 10 M) [87]. Other carbocyclic neuraminidase inhibitors include the guanidino substituted cyclohexene 39 [88] and amine derivatives [89] such as 40, which was found to be an inhibitor of influenza B neuraminidase comparable with oseltamivir 35, but was not as potent against influenza A virus [89a]. 

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