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The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I]500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) =0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).

The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The ketomethylene-containing inhibitors typically display slightly reduced 3CP inhibition activity relative to the corresponding peptide-derived molecules, but they also exhibit significantly improved antiviral properties. Optimization of the ketomethylene-containing compounds is shown to provide several highly active 3C protease inhibitors which function as potent antirhinoviral agents (EC90 =1 microM) against multiple virus serotypes in cell culture.

The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (kobs/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 microM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (kobs/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 microM). A 1.9 A crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.

The reaction of CpHfCl 3 •2THF with 2 equiv of (1,2,3-Me 3 allyl)MgBr or (1,1,2-Me 3 allyl)MgBr yields Cp(1,2,3-Me 3 allyl)(1,2-Me 2 butadiene)Hf (3) or Cp(1,1,2-Me 3 allyl)(2,3-Me 2 butadiene)Hf (4). X-ray crystallography of 3 shows that both the allyl and butadiene ligands assume a prone orientation with respect to Cp. Variable-temperature 1 H NMR studies indicate that compound 3 is static on the NMR time scale whereas 4 exists in two isomeric forms and undergoes three separate dynamic processes involving η 3 -η 1 isomerization at the unsubstituted and substituted ends of the allyl ligand [ΔG : =39.4±1.0 kJ/mol and 73.4±1.0 kJ/mol, respectively] and butadiene flip [ΔG : (avg)=49.8±10. kJ/mol]