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US 6,204,279 B1Granted
Peptidomimetic efflux pump inhibitors
AssigneeMicrocide Pharmaceuticals, Inc.
InventorsRoger Leger, Ving J. Lee, Miles She
Life of this patent
Estimating the term…
Abstract
Compounds are described which have efflux pump inhibitor activity. Also described are methods of using such efflux pump inhibitor compounds and pharmaceutical compositions which include such compounds.
Claims22
A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, comprising contacting said microbe with said antimicrobial agent and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in said microbe, wherein said efflux pump inhibitor has the chemical structure:
- wherein;
- M* is selected from the group consisting of (CH2)n, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;
- R and R1 are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, alyl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH2)nNRbRc, (CH2)nNHC═(NRa)NRbRc, (CH2)nSC═(NRa)NRbRc, (CH2)nC═(NRa)NRbRc, and (CH2)nN═C(H)NRbRc, wherein n is 1, 2, 3, or 4;
- Ra, Rb, and Rc are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or Ra and Rb or Rb and Rc taken together form a group selected from the group consisting of (CH2)2-3 and —CH═CH—;
- R3 and R4 are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;
- W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino;
- and
- where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.
5 more elements
A pharmaceutical composition effective for treatment of an infection of an animal by a microbe, comprising an efflux pump inhibitor, an antimicrobial agent and a pharmaceutically acceptable carrier, wherein said efflux pump inhibitor has the chemical structure:
- wherein:
- M* is selected from the group consisting of (CH2)n, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;
- R and R1 are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroallyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH2)nNRbRc, (CH2)nNHC═(NRa)NRbRc, (CH2)nSC═(NRa)NRbRc, (CH2)nC═(NRa)NRbRc, and (CH2)nN═C(H)NRbRc, wherein n is 1, 2, 3, or 4;
- Ra, Rb, and Rc are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or Ra and Rb or Rb and Rc taken together form a group selected from the group consisting of (CH2)2-3 and —CH═CH—;
- R3 and R4 are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;
- W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino;
- and
- where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.
5 more elements
A method of suppressing growth of a bacterium expressing an efflux pump, comprising contacting said bacterium with an efflux pump inhibitor in the presence of a concentration of antibacterial agent below the MIC of said bacterium, wherein said efflux pump inhibitor has the chemical structure:
- wherein:
- M* is selected from the group consisting of (CH2)n,and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;
- R and R1 are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH2)nNRbRc, (CH2)nNHC═(NRa)NRbRc, (CH2)nSC═(NRa)NRbRc, (CH2)nC═(NRa)NRbRc, and (CH2)nN═C(H)NRbRc, wherein n is 1, 2, 3, or 4;
- Ra, Rb, and Rc are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or Ra and Rb or Rb and Rc taken together form a group selected from the group consisting of (CH2)2-3 and —CH═CH—;
- R3 and R4 are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;
- W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkyltho, guanidino, and amidino;
- and
- where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.
5 more elements
An efflux pump inhibitor compound, wherein said compound has the chemical structure:
- wherein:
- M* is selected from the group consisting of (CH2)N, and CH(OH), wherein the carbon can have either R- or S-configuration, and wherein n is 0, 1, or 2;
- R and R1 are independently selected from the group consisting of H, lower alkyl, branched alkyl, fluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH2)nNRbRc, (CH2)nNHC═(NRa)NRbRc, (CH2)nSC═(NRa)NRbRc, (CH2)nC═(NRa)NRbRc, and (CH2)nN═C(H)NRbRc, wherein n is 1, 2, 3, or 4;
- Ra, Rb, and Rc are independently selected from the group consisting of H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxyl, and nitro, or Ra and Rb or Rb and Rc taken together form a group selected from the group consisting of (CH2)2-3 and —CH═CH—;
- R3 and R4 are independently selected from the group consisting of H, lower alkyl, branched alkyl, halogen, aryl, arylalkyl, thienylalkyl, furylalkyl, alkoxyl, alkylthio, aryloxy, and arylthio;
- W is selected from the group consisting of amino, azaheterocycles, substituted azaheterocycles, hydroxyl, alkoxy, alkylthio, guanidino, and amidino;
- and
- where there are centers of asymmetry, the absolute stereochemistry can be either R or S- configuration or any combination of configurations.
5 more elements
Dependencies are inferred from the claim text.