Sialidase Inhibitors Based on a Five-Membered Ring Scaffold

Sialidase Inhibitors Based on a Five-Membered Ring Scaffold 

Whereas cyclohexene or benzene ring systems are intuitively apparent mimics of Neu5Ac2en and related inhibitors, it is less obvious that five-membered ring systems can play the same role. However, it has been demonstrated that compounds based on different five-membered cyclic scaffolds can engage each of the identified subsites (S1-S5) of influenza virus NA, affording potent inhibitory activity. 

BCX-1812, also known as Peramivir and RWJ-270201, successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was administrated orally, showing neither major side effects nor toxicity.137 However, in Phase III trial, Peramivir did not show statistical efficacy, presumably because of a lack of bioavailability. Recently the efficacy of 

The functionalized cyclopentane 178 (BCX-1827) displayed similar activity to 174, exhibiting potent anti-influenza virus effects both in vitro in MDCK cells and in vivo in a mouse model.139 141 

In vitro test data for the best candidates 179-182 showed low pM activity for the inhibition of NA(A) but diminished activity towards NA(B), displayed IC50 values for 179 0.08 pM and 3pM, 180 0.015 pM and 3pM, 181 0.06 pM and 9.2 pM, and 182 0.04 pM and 7.8 pM, against NA(A) and NA(B), respectively.142 These results were comparable to the results reported for the amides of Zanamivir type. The active stereoisomer of 180 was found to have the 

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