Methods and compounds for treatment of clostridium based infection
Inventors
Guiles, Joseph • Sun, Xicheng • Janjic, Nebojsa • STRONG, Sarah
Assignees
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Publication Number
US-8658670-B2
Publication Date
2014-02-25
Expiration Date
Abstract
Methionyl tRNA synthetase inhibitors (MetRS) are provided for use in therapy as antibacterial agents in Clostridium based infection.
Core Innovation
The invention provides a method of treating a Clostridium difficile based infection in a mammal by administering an effective amount of a MetRS inhibitor compound. The MetRS inhibitor is a compound represented by formula (IIa), with defined structural variables and stereochemical configuration rules tied to the asymmetric carbon atom indicated by “*”.
The compound class for formula (IIa) defines X as NH, O, S, SO, SO2, or CH2, with n selected from 1, 2, or 3 and m selected from 0, 1, 2, 3, or 4. R1 and R2 are independently selected from halo, cyano, hydroxyl, (C1-6)alkyl, (C3-7)cycloalkyl, C(1-6)alkoxy, amino, mono- or di-(C1-6)alkylamino, acylamino, carboxy, (C1-6)alkoxycarbonyl, carboxy(C1-6)alkyloxy, (C1-6)alkylthio, (C1-6)alkylsulphinyl, (C1-6)alkylsulphonyl, sulphamoyl, mono- and di-(C1-6)alkylsulphamoyl, carbamoyl, mono- and di-(C1-6)alkylcarbamoyl and heterocyclic.
Additional rules specify when Z1 is S, Z2 and Z3 are CH; when Z2 is S, Z1 and Z3 are CH; and when Z3 is S, Z1 and Z2 are CH. The described therapeutic utility includes inhibition of Clostridium difficile growth, toxin production including TcdA and TcdB and the binary toxin cdtA/cdtB, and spore formation.
Claims Coverage
The document contains one independent claim and one dependent claim. Across these claims, there are two main inventive features: treatment of a Clostridium difficile based infection in a mammal, and a defined MetRS inhibitor of formula (IIa) with specified structural and stereochemical constraints.
Treating a Clostridium difficile based infection in a mammal with a MetRS inhibitor
A method of treating a Clostridium difficile based infection in a mammal comprising administering to the mammal an effective amount of a MetRS inhibitor compound.
MetRS inhibitor defined as a compound of formula (IIa) with specified structural and stereochemical constraints
The MetRS inhibitor is represented by formula (IIa), in which X is NH, O, S, SO, SO2, or CH2, n is 1, 2 or 3, m is 0, 1, 2, 3, or 4, R1 and R2 are independently selected from the listed substituent groups, and the Z1/Z2/Z3 relationship is constrained as stated.
Selecting the MetRS inhibitor from a defined group of specific compounds
The method of claim 1 in which the MetRS inhibitor is selected from a defined group of specific MetRS inhibitor chemical compounds.
Overall, the claim set covers treating a Clostridium difficile based infection in a mammal using an effective amount of a MetRS inhibitor, where the inhibitor is defined by formula (IIa) with explicit structural-variable definitions and stereochemical configuration rules, and dependent coverage further restricts the inhibitor to specific compounds.
Stated Advantages
Inhibition of Clostridium difficile growth.
Inhibition of toxin production, including TcdA and TcdB and the binary toxin cdtA/cdtB.
Inhibition of spore formation.
In vivo hamster efficacy versus vancomycin, with increased survival.
Documented Applications
Treatment of Clostridium difficile based infection in a mammal, including CDAD (Clostridium difficile associated diarrhea), pseudomembranous colitis, and toxic megacolon.
Antibacterial use of MetRS (methionyl-tRNA synthetase) inhibitors as agents targeting bacterial MetRS with selectivity over mammalian MetRS.
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