PEPTIDOMIMETIC INHIBITORS OF HERPES-SIMPLEX VIRUS RIBONUCLEOTIDE REDUCTASE WITH IMPROVED IN-VIVO ANTIVIRAL ACTIVITY

We have been investigating the potential of a new class of antiviral c ompounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (R R), an enzyme necessary for efficient replication of viral DNA. The co mpounds disclosed in this paper build on our previously published work . Structure-activity studies reveal beneficial modifications that resu lt in improved antiviral potency in cell culture in a murine ocular mo del of HSV-induced keratitis. These modifications include a stereochem ically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethy lene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. T hese three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporati on of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantl y more potent antiviral compound than our previously published best co mpound, BILD 1263.