Cyclopentanebased inhibitors

The crystal structure of 20 and the activity of this compound against NA demonstrate that the relative position of the interacting groups is the most important factor for potent neuraminidase inhibition [61]. This observation suggested that a cyclopentane ring might be a suitable scaffold for a novel neuraminidase inhibitor. The first entry, 22, in this class of compounds was initially synthesized as a race-mate. Encouraged by the promising activity of this compound against the NA enzyme [61,63], compound 23 was synthesized to exploit the small hydrophobic surface in the active site of the NA enzyme. This compound was prepared initially as a mixture of eight isomers. The stereochemistry of the potent isomer from this mixture was identified from the crystal structure of 23 complexed with NA. The optimization of the hydrophobic side chains resulted in compounds 25a and 25b. Compounds 24a and 24b, obtained as intermediates during the synthesis of 25a and 25b, were found to possess activity similar to 25a and 25b [IC50 = 0.1-11 nM]. Among these compounds, 24a was selected for clinical development because of ease of synthesis [61]. Attempts to replace the alkyl side chain with amide (26) yielded compounds with good activity against NA from influenza A but not against influenza B [64]. Some compounds of type 27 were also prepared, but did not show good activity against neuraminidase [65].

co2h

HO NHCOCH3 20

co2h

HO NHCOCH3 20

CO2H

..iCO2H

H NHCOCH3

..iCO2H

H NHCOCH3

CO2H

alkyl n nhac nh2

CO2H

CO2H

NHCOCH3

NHCOCH3

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