title: Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability.
abstract: Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Le Tiran
authors.forename: Dean
authors.initials: D
authors.lastname: Shannon
authors.forename: Elaine
authors.initials: E
authors.lastname: Krueger
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Liao
authors.forename: Hardwin
authors.initials: H
authors.lastname: O'Dowd
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.forename: Steve
authors.initials: S
authors.lastname: Ronkin
authors.forename: Tiansheng
authors.initials: T
authors.lastname: Wang
authors.forename: Nathan
authors.initials: N
authors.lastname: Waal
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Lauffer
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sizensky
authors.forename: Jerry
authors.initials: J
authors.lastname: Tanoury
authors.forename: Emanuele
authors.initials: E
authors.lastname: Perola
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Brian
authors.initials: B
authors.lastname: Hanzelka
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Vaishali
authors.initials: V
authors.lastname: Dixit
authors.forename: Nigel
authors.initials: N
authors.lastname: Ewing
authors.forename: Shengkai
authors.initials: S
authors.lastname: Liao
authors.forename: Brian
authors.initials: B
authors.lastname: Boucher
authors.forename: Marc
authors.initials: M
authors.lastname: Jacobs
authors.forename: Youssef
authors.initials: Y
authors.lastname: Bennani
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D014508:Urea; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase