Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases

Timothy J Miles; Alan J Hennessy; Ben Bax; Gerald Brooks; Barry S Brown; Pamela Brown; Nathalie Cailleau; Dongzhao Chen; Steven Dabbs; David T Davies; Joel M Esken; Ilaria Giordano; Jennifer L Hoover; Graham E Jones; Senthill K Kusalakumari Sukmar; Roger E Markwell; Elisabeth A Minthorn; Steve Rittenhouse; Michael N Gwynn; Neil D Pearson

doi:10.1016/j.bmcl.2016.03.106

Novel tricyclics (e.g., GSK945237) as potent inhibitors of bacterial type IIA topoisomerases

Bioorg Med Chem Lett. 2016 May 15;26(10):2464-2469. doi: 10.1016/j.bmcl.2016.03.106. Epub 2016 Mar 31.

Authors

Timothy J Miles¹, Alan J Hennessy², Ben Bax³, Gerald Brooks⁴, Barry S Brown⁵, Pamela Brown², Nathalie Cailleau⁴, Dongzhao Chen⁵, Steven Dabbs², David T Davies⁴, Joel M Esken⁵, Ilaria Giordano⁶, Jennifer L Hoover⁵, Graham E Jones⁴, Senthill K Kusalakumari Sukmar⁵, Roger E Markwell⁴, Elisabeth A Minthorn⁷, Steve Rittenhouse⁵, Michael N Gwynn⁵, Neil D Pearson⁵

Affiliations

¹ Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain. Electronic address: tim.j.miles@gsk.com.
² Infectious Diseases CEDD, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
³ Platform Technology & Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
⁴ Infectious Diseases CEDD, GlaxoSmithKline, Third Avenue, Harlow CM19 5AW, UK.
⁵ Infectious Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
⁶ Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
⁷ Oncology TA, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.

PMID: 27055939
DOI: 10.1016/j.bmcl.2016.03.106

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.

Keywords: Antibacterials; Bacterial type IIA topoisomerase; GSK945237; In vivo efficacy; NBTI; Pharmacokinetic; Tricyclics.

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacokinetics
Anti-Bacterial Agents / pharmacology*
Chemistry Techniques, Synthetic
DNA Topoisomerases, Type II / chemistry
DNA Topoisomerases, Type II / metabolism
Dogs
Drug Evaluation, Preclinical / methods
ERG1 Potassium Channel / metabolism
Gram-Negative Anaerobic Bacteria / drug effects
Gram-Positive Bacteria / drug effects
Heterocyclic Compounds, 3-Ring / chemical synthesis
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology*
Heterocyclic Compounds, 4 or More Rings / chemistry*
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Pneumococcal Infections / drug therapy
Rats
Respiratory Tract Infections / drug therapy
Respiratory Tract Infections / microbiology
Topoisomerase II Inhibitors / chemistry*
Topoisomerase II Inhibitors / pharmacokinetics
Topoisomerase II Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
ERG1 Potassium Channel
GSK945237
Heterocyclic Compounds, 3-Ring
Heterocyclic Compounds, 4 or More Rings
KCNH2 protein, human
Topoisomerase II Inhibitors
DNA Topoisomerases, Type II