Peptidomimetic Inhibitors of Herpes Simplex Virus Ribonucleotide Reductase with Improved in Vivo Antiviral Activity

• Published in: Journal of medicinal chemistry Vol. 39; no. 21; pp. 4173 - 4180
• Main Authors: Moss, Neil, Beaulieu, Pierre, Duceppe, Jean-Simon, Ferland, Jean-Marie, Garneau, Michel, Gauthier, Jean, Ghiro, Elise, Goulet, Sylvie, Guse, Ingrid, Jaramillo, Jorge, Llinas-Brunet, Montse, Malenfant, Éric, Plante, Raymond, Poirier, Martin, Soucy, Francois, Wernic, Dominik, Yoakim, Christiane, Déziel, Robert
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.10.1996; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Dipeptides - chemistry; Dipeptides - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; herpes simplex virus; Keratitis, Herpetic - drug therapy; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Oligopeptides - chemistry; Oligopeptides - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Ribonucleotide Reductases - antagonists & inhibitors; Science & Technology; Simplexvirus - drug effects; Simplexvirus - enzymology; Stereoisomerism; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; SENSITIVITY; TERMINUS; PEPTIDES; DERIVATIVES; COLORIMETRIC ASSAY; SUBUNIT; Keratitis; Peptides; Enzyme; Herpesviridae; Peptidomimetic compound; Alphaherpesvirinae; Rodentia; Enzyme inhibitor; In vitro; Virus; Eye disease; Vertebrata; Experimental disease; Mammalia; Structure activity relation; Ribonucleoside-triphosphate reductase; Mouse; Tetrapeptide; Animal; Antiviral; Herpesvirus hominis; Oxidoreductases; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960324r

We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure−activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.