title: Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile.
abstract: Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.
authors.affiliation: Actelion Pharmaceuticals Limited , Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Surivet
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zumbrunn
authors.forename: Georg
authors.initials: G
authors.lastname: Rueedi
authors.forename: Daniel
authors.initials: D
authors.lastname: Bur
authors.forename: Thierry
authors.initials: T
authors.lastname: Bruyère
authors.forename: Hans
authors.initials: H
authors.lastname: Locher
authors.forename: Daniel
authors.initials: D
authors.lastname: Ritz
authors.forename: Peter
authors.initials: P
authors.lastname: Seiler
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ertel
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Gauvin
authors.forename: Azely
authors.initials: A
authors.lastname: Mirre
authors.forename: Verena
authors.initials: V
authors.lastname: Kaegi
authors.forename: Marina
authors.initials: M
authors.lastname: Dos Santos
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Kraemer
authors.forename: Mika
authors.initials: M
authors.lastname: Gaertner
authors.forename: Jonathan
authors.initials: J
authors.lastname: Delers
authors.forename: Michel
authors.initials: M
authors.lastname: Enderlin-Paput
authors.forename: Maria
authors.initials: M
authors.lastname: Weiss
authors.forename: Romain
authors.initials: R
authors.lastname: Sube
authors.forename: Hakim
authors.initials: H
authors.lastname: Hadana
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Keck
authors.forename: Christian
authors.initials: C
authors.lastname: Hubschwerlen
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011714:Pyrans; D059005:Topoisomerase II Inhibitors