Influenza virus sialidase inhibitors

Further Developments of Influenza Virus Sialidase Inhibitors. 123... 

India, medicinal research in, 22 (1985) 243 Influenza virus sialidase, inhibitors of, 36 (1999) 1... 

Carbon-carbon bond lyases, used in the reverse, synthetic direction have also enjoyed significant application in the pharmaceutical industry. For example 7/-acetyl-D-neuraminic acid (NANA), an intermediate in the chemoenzymatic synthesis of the influenza virus sialidase inhibitor zanamavir, may be synthesized using NANA aldolase. 

Influenza Virus Sialidase Inhibitors Based on an Aromatic Scaffold 323... 

The discovery of Zanamivir as a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis and structure-activity relationship studies of Neu5Ac2en-based compounds as potential sialidase inhibitors. Exploration of these SAR studies were undertaken to optimize inhibitory activity and to improve the physicochemical properties of the sialic acid-based influenza virus sialidase inhibitor. A few in vitro assays are commonly employed to measure the effectiveness of influenza virus sialidase inhibitors. The first involves a fluorometric assay that measures release of a synthetic fluorophore following its cleavage from Neu5Ac by sialidase. Dye-uptake assay, such as the Neutral Red uptake assay, measures the uptake of a vital stain, Neutral Red in cell culture. The process requires intact membranes and active metabolism in the cell, and is expressed as percent protective rate against virus infection. The plaque-reduction assay is used to measure sialidase inhibition indirectly in cell culture, and provides some measure of the inhibitor s effect on the viability of the influenza virus. In vitro and in vivo systems for analysis of inhibitors of influenza virus enzymes have been reviewed.71... 

M. von Itzstein, W. Y. Wu, and B. Jin, The synthesis of 2,3-didehydro-2,4-dideoxy-4-guanidinyl-V-acetylneuraminic acid A potent influenza virus sialidase inhibitor, Carbohydr. Res., 259 (1994) 301-305. 

X-ray crystal structures of a-Neu5Ac and 11 in complex with influenza virus sialidases in the 1980s and early 1990s led to the opportunity for structure-based design and development of influenza virus sialidase inhibitors [66, 85],... 

In the challenge to develop potent influenza virus sialidase inhibitors, a large amount of research has been dedicated to the manipulation of every position on 11 except C3. Structure-activity relationship (SAR) studies carried out on compounds derived from 11 before and during the development of zanamivir (reviewed in [101-103]) revealed structural requirements to conserve the main interactions between the substrate inhibitor and the active site of NA, particularly with regards to the carboxylate, C4-guanidino, and C5-acetamido moieties. 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

Another remarkable influenza virus sialidase inhibitor, derivative 25 [119], was developed based on a pyrrolidine core by Abbott Laboratories [119, 123], X-ray crystal studies surprisingly observed hydrophobic interactions of the d.s-propenyl group within S2, which is normally involved in charge-charge interaction as with the guanidino moiety in zanamivir [69], The side-chain methyl and methoxy groups of... 

NEW INFLUENZA VIRUS SIALIDASE INHIBITORS TARGETING THE 150-CAVITY... 

Kok, G B, Campbell, M, Mackey, B, von Itzstein, M, Synthesis and biological evaluation of sulfur isosteres of the potent influenza virus sialidase inhibitors 4-amino-4-deoxy- and 4-deoxy-4-guanidino-Neu5Ac2en, J. Chem. Soc., Perkin. Trans. 1, 2811-2815, 1996. 

Compounds 373 and 374, thio isosteres of potent influenza virus sialidase inhibitors (IC50 values of 1 x 10 M and 5 x 10 M, respectively), were found to be as bioactive as their oxygen counterparts. 

Several excellent articles describing various aspects of influenza virus, both with respect to the virus itself as well as approaches towards the development of anti-influenza agents, have been published in recent years [4-16]. In view of the comprehensive nature of these reports it is the aim of this account, apart from providing the background information necessary to a fundamental understanding of influenza, to focus on advances in the development of influenza virus sialidase inhibitors over the last decade. ... 

The first substrate-based influenza virus sialidase inhibitor described was Neu5Ac2en (6) [71, 72], It is proposed that the olefin in (6) mimics, to a certain extent, the conformation of the proposed sialosyl cation transition-state intermediate (4) [62,68,69], Neu5Ac2en shows reasonably potent inhibition of influenza virus sialidase (with a A j in the range of 10 5 to 10 6 M) in vitro... 

Other carbohydrate based analogues of zanamivir which have been synthesized as potential influenza virus sialidase inhibitors include the sulfur isostere (37), which was prepared from the known [113] 6-thio-Neu5Ac derivative (38) via a sequence analogous to that shown in Scheme 1.2 for the preparation of zanamivir [114]. The sulphur isostere (37) was found to have comparable activity (IC50 = 5 x 10 9 M) to zanamivir [114]. 

Of all the influenza virus sialidase inhibitors based on zanamivir reported to date, the most promising compounds are those which contain a carbocyc-lic ring in place of the dihydropyran ring. Early work in this regard involved the use of Diels-Alder chemistry to ultimately provide access to the side-... 

Another class of potent and selective influenza virus sialidase inhibitors which are orally active against influenza A and B, based on a cyclopentane framework, have also been described [54], Although not yet commercially available, BCX-1812 (RWJ-270201,5) has been subjected to Phase III clinical trials. BCX-1812 (5) is a nanomolar inhibitor of both influenza virus A and B sialidase and inhibits growth of influenza virus in tissue culture [55] and has demonstrated efficacy in a mouse influenza model... 

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