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Selective Inhibitors of Human Neuraminidase 1 (NEU1)

Inhibitors of human neuraminidase enzymes (NEU) are recognized as important tools for the study of the biological functions of NEU and will be potent tools for elucidating the role of these enzymes in regulating the repertoire of cellular glycans. Here we report the discovery of selective inhibitors of the human neuraminidase 1 (NEU1) and neuraminidase 2 (NEU2) enzymes with exceptional potency. A library of modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) analogues, with variability in the C5- or C9-position, were synthesized and evaluated against four human neuraminidase isoenyzmes (NEU1-4). Hydrophobic groups with an amide linker at the C5 and C9 positions were well accommodated by NEU1, and a hexanamido group was found to give the best potency at both positions. While the C5-hexanamido-C9-hexanamido-DANA analogue did not show synergistic improvements for combined modification, an extended alkylamide at an individual position combined with a smaller group at the second gave increased potency. The best NEU1 inhibitor identified was a C5-hexanamido-C9-acetamido-DANA that had a Ki of 53 ± 5 nM and 340-fold selectivity over other isoenzymes. Additionally, we demonstrated that C5-modifications combined with a C4-guandino group provided the most potent NEU2 inhibitor reported, with a Ki of 1.3 ± 0.2 μM and 7-fold selectivity over other NEU isoenzymes.

Compounds useful for inhibiting paramyxovirus neuraminidase

Compounds represented by the formula: wherein X is selected from the group consisting of: CHR, O, NR, N—OR, NR(O), S, S(O) and S(O)O X1 is selected from the group consisting of CR, N, and N(O); R is selected from the group consisting of: H, alkyl, alkene, alkyne, CN, NO2, N3, halo and NHR10; R1 is selected from the group consisting of: H, (CH2)nCO2R10, (CH2)n-tetrazol, (CH2)nSO3H, (CH2)nSO2H, (CH2)nPO3H2, (CH2)nCONR10, (CH2)nNO2, and (CH2)nCHO; R1a is selected from the group consisting of: H, (CH2)nOR10, (CH2)nCN, (CH2)nNR10R10a, (CH2)nNHC(O)R10, (CH2)nC(O)NR10R10a, and (CH2)nOC(O)R10; R1 and R1a both cannot be H each of R2 and R2a is independently selected from the group consisting of H, halo, CN, (CH2)nCO2R10, (CH2)nNR10R10a and (CH2)n—OR10; each of R3 and R3a is independently selected from the group consisting of: H, NHSO2R10, N(O)—SO2R10, NR10SO2R10a, (CH2)mYR10, and (CH2)mR6; at least one of R3 and R3a should be other than H Y is selected from the group consisting of: O, NH, NHC(O), C(O)NH, S, S(O), S(O)O, NHS(O)O, S(O)ONH, NHC(O)NH and heterocycle; R3 and R3a together may be ═O, ═CHR6, ═CHR10, ═NR10, NR10 and ═N—OR10 R4 and R4a is independently selected from the group consisting of: H, (CH2)mYR10 and (CH2)mR6 R4 and R4a together may be: ═O, ═CHR6, ═CHR10, ═NR10 and ═N—OR10 each of R5 and R5a is independently selected from the group consisting of C(R7)(R7a), C(R7)(R7a)C(R8)(R8a), C(R7)(R7a)C(R8)(R8a)C(R9)(R9a), OC(R7)(R7a), OC(R7)(R7a)C(R8)(R8a), C(R7)(R7a)OC(R8)(R8a), N(R10)C(R7)(R7a), N(R10) C(R7)(R7a)C(R8)(R8a), C(R7)(R7a)N(R10)C(R8)(R8a), and C(O)NR10R10a; R6 is selected from the group consisting of H, halo, CN, NO2, N3, CO2R10, R10 and NR10R10a; R7, R7a, R8, R8a, R9 and R9a is selected from the group from the group consisting of: H, (CH2)mYR10 and (CH2)mR6 each of the R10 and R10a is individually selected from the groups consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; Each of m and n is individually 0, 1, 2, 3, or 4; and pharmaceutically acceptable salt thereof; and prodrugs thereof, and uses thereof.