title: Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.
abstract: Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Hardwin
authors.initials: H
authors.lastname: O'Dowd
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dean E
authors.initials: DE
authors.lastname: Shannon
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Kishan R
authors.initials: KR
authors.lastname: Chandupatla
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Dixit
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Juntyma J
authors.initials: JJ
authors.lastname: Engtrakul
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Zhengqi
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jones
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Colleen F
authors.initials: CF
authors.lastname: O'Brien
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, Connecticut 06102, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, Connecticut 06102, United States.
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Tessier
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital , 80 Seymour Street, Hartford, Connecticut 06102, United States.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Dainius
authors.initials: D
authors.lastname: Macikenas
authors.affiliation: Vertex Pharmaceuticals Incorporated , 2500 Crosspark Road, Bioventures Center, Coralville, Iowa 52241, United States.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hanzelka
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Le Tiran
authors.affiliation: Vertex Pharmaceuticals Incorporated , 275 Boulevard Armand Frappier, Laval, QC H7V 4A7, Canada.
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Charifson
authors.affiliation: Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Grillot
keywords: DNA gyrase; Prodrug; topoisomerase IV; water soluble