title: Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases.
abstract: During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
authors.affiliation: Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain. Electronic address: tim.j.miles@gsk.com.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Miles
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Hennessy
authors.affiliation: Platform Technology & Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Bax
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brooks
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Brown
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Brown
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cailleau
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Dongzhao
authors.initials: D
authors.lastname: Chen
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Dabbs
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Davies
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Esken
authors.affiliation: Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giordano
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hoover
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Jones
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Senthill K
authors.initials: SK
authors.lastname: Kusalakumari Sukmar
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
authors.forename: Roger E
authors.initials: RE
authors.lastname: Markwell
authors.affiliation: Oncology TA, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Minthorn
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Rittenhouse
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gwynn
authors.affiliation: Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
authors.forename: Neil D
authors.initials: ND
authors.lastname: Pearson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel / Q000378:metabolism; D006089:Gram-Negative Anaerobic Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology*; D011008:Pneumococcal Infections / Q000188:drug therapy; D051381:Rats; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; C000624887:GSK945237; D006575:Heterocyclic Compounds, 3-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; C000606913:KCNH2 protein, human; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Antibacterials; Bacterial type IIA topoisomerase; GSK945237; In vivo efficacy; NBTI; Pharmacokinetic; Tricyclics