title: Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity.
abstract: 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.
authors.affiliation: Bio-Méga/Boehringer Ingelheim Research Inc., Laval, Québec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Moss
authors.forename: P
authors.initials: P
authors.lastname: Beaulieu
authors.forename: J S
authors.initials: JS
authors.lastname: Duceppe
authors.forename: J M
authors.initials: JM
authors.lastname: Ferland
authors.forename: M
authors.initials: M
authors.lastname: Garneau
authors.forename: J
authors.initials: J
authors.lastname: Gauthier
authors.forename: E
authors.initials: E
authors.lastname: Ghiro
authors.forename: S
authors.initials: S
authors.lastname: Goulet
authors.forename: I
authors.initials: I
authors.lastname: Guse
authors.forename: J
authors.initials: J
authors.lastname: Jaramillo
authors.forename: M
authors.initials: M
authors.lastname: Llinas-Brunet
authors.forename: E
authors.initials: E
authors.lastname: Malenfant
authors.forename: R
authors.initials: R
authors.lastname: Plante
authors.forename: M
authors.initials: M
authors.lastname: Poirier
authors.forename: F
authors.initials: F
authors.lastname: Soucy
authors.forename: D
authors.initials: D
authors.lastname: Wernic
authors.forename: C
authors.initials: C
authors.lastname: Yoakim
authors.forename: R
authors.initials: R
authors.lastname: Déziel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016849:Keratitis, Herpetic / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; C090897:BILD 1263; C101890:BILD 1351; C101891:BILD 1357; D004151:Dipeptides; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D014508:Urea; D012264:Ribonucleotide Reductases