NA inhibitor

Tisdale M (2000) Monitoring of viral susceptibility new challenges with the development of influenza NA inhibitors. Rev Med Virol 10 45-55... 

Two classes of inhibitors for influenza virus are currently available (Hayden 2006). The M2 proton channel inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors oseltamivir carboxylate and zanamivir. Chapter 5 provides more details about the class of NA inhibitors. 

The worldwide spread of H5N1 avian influenza virus has raised the concern of its potential to emerge as a human-adapted virus. Three decades of intense research have yielded only two NA inhibitors, Relenza and Tamiflu , that... 

Several NA inhibitor analogues have been synthesised using structure of DANA 6 as a base molecule. An extremely potent influenza NA inhibitor, with Ki value of 10 M, is 2,3-didehydro-2,4-dideoxy-4-guanyl-N-acetylneuraminic acid 7, Zanamivir, GG167, fig. (12) [33,34,35]. 

Therefore, it would be desirable to have a new class of orally active NA inhibitors as potential agents against influenza infection. 

The general approach to the structure-based design of NA inhibitors uses the structure of the DANA - NA complex as a starting point and it is based on the development of new classes of lead compounds by using chemically simpler cyclic templates instead of the dihydropyran ring of DANA. 

It has been proposed that simple non-carbohydrate analogues containing the carboxylate and the acetylamino groups attached to a cyclic backbone spacer would be suflSdent to generate lead compoimds for further elaboration as NA inhibitors. The spacer would need to orient correctly these groups as found in bound DANA. It has been also required thad such compounds adopt a planar structure near the carboxylate to mimic the transition state and be able to present additional side-chain functionality for interaction with other conserved amino acid residues in the sialic acid binding site. 

Therefore, designing a new series of NA inhibitors, has been a try to mimic this planar arrangement of substituents using a benzene ring as a replacement for the dihydropyran ring in GG167. 

Recently, simple aromatic influenza NA inhibitors have been synthesised [42]. Compound 8 is the most important aromatic analogue of DANA. In fact it inhibits influenza A sialidase with a Kj of 2.5 pM. Compound 8 has been synthesised [43] as described in the Scheme H. 

The validity of this approach has been verified by the discovery of very potent NA inhibitors in this new carbocyclic series. In particular new lipophilic side chains at the C-3 position of the carbocyclic system inq)arted potent NA inhibitory activity. In fact X-ray crystallographic anal)rsis of the carbocyclic analogue bound to NA confirmed that there is an hydrophobic space in the glycerol-binding subsite to accommodate bulky lipophilic groups. 

In this new class of DANA s analogues, the most potent NA inhibitor is GS4071,12, fig. (15), with IC50 of InM. 

A new NA inhibitor, 16, of influenza sialidase has been recently designed [51], see fig 17, whose molecule consists in the combination of an aromatic moiety with a y-lactame. Its structure is that of a l-(4-carboxy-2-(3-pentylamino)phenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one. 

Syntheses of the Prototypes In their initial stage of designing carbocyclic NA inhibitors, the oleflnic isomers that are shown in structures 109 (Type [I]) and 110 (Type [II]) were considered as two possible prototypes of transition-state analogues. The isomer 109 is structurally closer to transition-state 108 than isomer 110. However, Gilead s group expected that it would be... 

It was concluded that this result demonstrated that the double bond position in the design of carbocyclic NA inhibitors plays an important role in NA activity however, further structural investigation is required to illustrate the binding differences of 109a and 110a in the NA active site. Eventually, based on this result, the stmcture of 109 was selected as the prototype for further drug discovery attempts. 

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