Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P-1 lactam moieties as L-glutamine replacements

The structure-based design, chemical synthesis, and biological evaluation o f various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorpo rate P-1 lactam moieties in lieu of an L-glutamine residue are described. T hese compounds are comprised of a tripeptidyl or peptidomimetic binding det erminant and an ethyl propenoate Michael acceptor moiety which forms an irr eversible covalent adduct with the active site cysteine residue of the 3C e nzyme. The P-1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties rela tive to corresponding L-glutamine-derived molecules. In addition, several l actam-containing compounds exhibit excellent selectivity for HRV 3CP over s everal other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG70 88, mean antirhinoviral EC90 0.10 approximate to mu M, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potenti al for use as an antirhinoviral agent.