title: The design, synthesis and properties of highly potent and selective inhibitors of herpes simplex virus types 1 and 2 thymidine kinase.
abstract: The rational design and synthesis of nucleotide analogues as inhibitors of herpes simplex virus (HSV) thymidine kinase is described. Starting from thymidine, product analogues which included phosphates, phosphonates, sulphonates, sulphonamides and carboxamides were prepared. The carboxamide series showed good structure-activity relationships and afforded a lead structure which inhibited the HSV-2 enzyme in the low micromolar range. Replacing the 5-methyl group in thymidine by ethyl enhanced the potency of the lead structure 10-fold. Further optimization of the carboxamide moiety afforded inhibitors active in the sub-nanomolar range and finally the introduction of a 2'-beta-fluoro substituent improved the potency a further twofold. The low water solubility of the most potent inhibitor was overcome by conversion to the 3'-valyl ester, which had good oral bioavailability and showed activity by the oral route in murine models of infection.
authors.affiliation: Department of Medicinal Chemistry, Roche Discovery Welwyn, Herts, UK. joseph.martin@roche.com
authors.forename: J A
authors.initials: JA
authors.lastname: Martin
authors.forename: G J
authors.initials: GJ
authors.lastname: Thomas
authors.forename: J H
authors.initials: JH
authors.lastname: Merrett
authors.forename: R W
authors.initials: RW
authors.lastname: Lambert
authors.forename: D J
authors.initials: DJ
authors.lastname: Bushnell
authors.forename: S J
authors.initials: SJ
authors.lastname: Dunsdon
authors.forename: A C
authors.initials: AC
authors.lastname: Freeman
authors.forename: R A
authors.initials: RA
authors.lastname: Hopkins
authors.forename: I R
authors.initials: IR
authors.lastname: Johns
authors.forename: E
authors.initials: E
authors.lastname: Keech
authors.forename: H
authors.initials: H
authors.lastname: Simmonite
authors.forename: P W
authors.initials: PW
authors.lastname: Kai-In
authors.forename: M
authors.initials: M
authors.lastname: Holland
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D018258:Herpesvirus 2, Human / Q000201:enzymology*; D006801:Humans; D013058:Mass Spectrometry; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D013937:Thymidine Kinase