Acyl phosphonate inhibitors of β-lactamases
View Patent ↗The invention provides novel β-lactamase inhibitors, which are structurally unrelated to the natural product and semi-synthetic β-lactamase inhibitors presently available, and which do not possess a β-lactam pharmacophore. These new inhibitors are fully synthetic, allowing ready access to a wide variety of structurally related analogs. Certain embodiments of these new inhibitors also bind bacterial DD-peptidases, thus potentially acting both as β-lactamase inhibitors and as antibiotics.
1. A β-lactamase inhibitor of Formula II:
wherein Y is O or alkylene, and X is alkylene, cycloalkylene, or arylene, wherein the alkylene, cycloalkylene, and arylene groups may be optionally substituted; provided that X is not phenylethene.
2. The inhibitor according to claim 1 , wherein X is phenylene.
3. A pharmaceutical composition, comprising a β-lactamase inhibitor of Formula II:
wherein Y is O or alkylene, and X is alkylene, cycloalkylene, or arylene, wherein the alkylene, cycloalkylene, and arylene groups may be optionally substituted; and a pharmaceutically acceptable carrier, diluent, or excipient.
4. The composition according to claim 3 , wherein X is phenylene.
5. A pharmaceutical composition, comprising a β-lactamase inhibitor having the structure:
and salts thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.
6. The composition according to claim 3 , further comprising an antibiotic agent.
7. The composition according to claim 6 , wherein the antibiotic agent is a β-lactam antibiotic.
8. A method for inhibiting bacterial growth, comprising administering a β-lactamase inhibitor of Formula II:
wherein Y is O or alkylene, and X is alkylene, cycloalkylene, or arylene, wherein the alkylene, cycloalkylene, and arylene groups may be optionally substituted.
9. The method according to claim 8 , wherein X is phenylene.
10. A method for inhibiting bacterial growth, comprising administering a β-lactamase inhibitor selected from the group consisting of:
and salts thereof.
11. The method according to claim 8 , further comprising administering an antibiotic agent.
12. The method according to claim 11 , wherein the antibiotic agent is a β-lactam antibiotic.
13. The composition according to claim 5 , further comprising an antibiotic agent.
14. The composition according to claim 13 , wherein the antibiotic agent is a β-lactam antibiotic.
15. The method according to claim 10 , further comprising administering an antibiotic agent.
16. The method according to claim 14 , wherein the antibiotic agent is a β-lactam antibiotic.