title: New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease.
abstract: The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.
authors.affiliation: Bayer AG, Pharma Research, Wuppertal, Germany. gerald.kleymann@freenet.de
authors.forename: Gerald
authors.initials: G
authors.lastname: Kleymann
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Fischer
authors.forename: Ulrich A K
authors.initials: UA
authors.lastname: Betz
authors.forename: Martin
authors.initials: M
authors.lastname: Hendrix
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bender
authors.forename: Udo
authors.initials: U
authors.lastname: Schneider
authors.forename: Gabriele
authors.initials: G
authors.lastname: Handke
authors.forename: Peter
authors.initials: P
authors.lastname: Eckenberg
authors.forename: Guy
authors.initials: G
authors.lastname: Hewlett
authors.forename: Veniamin
authors.initials: V
authors.lastname: Pevzner
authors.forename: Judith
authors.initials: J
authors.lastname: Baumeister
authors.forename: Olaf
authors.initials: O
authors.lastname: Weber
authors.forename: Kerstin
authors.initials: K
authors.lastname: Henninger
authors.forename: Jörg
authors.initials: J
authors.lastname: Keldenich
authors.forename: Axel
authors.initials: A
authors.lastname: Jensen
authors.forename: Jörg
authors.initials: J
authors.lastname: Kolb
authors.forename: Ute
authors.initials: U
authors.lastname: Bach
authors.forename: Andreas
authors.initials: A
authors.lastname: Popp
authors.forename: Jutta
authors.initials: J
authors.lastname: Mäben
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frappa
authors.forename: Dieter
authors.initials: D
authors.lastname: Haebich
authors.forename: Oswald
authors.initials: O
authors.lastname: Lockhoff
authors.forename: Helga
authors.initials: H
authors.lastname: Rübsamen-Waigmann
mesh_terms: D000212:Acyclovir / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006168:Guinea Pigs; D006561:Herpes Simplex / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011247:Pregnancy; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012449:Safety; D013449:Sulfonamides; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014764:Viral Proteins
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D013844:Thiazoles; D014764:Viral Proteins; C453221:pritelivir; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases; D000212:Acyclovir