Fluorocyclines. 2. Optimization
of the C-9 Side-Chain for Antibacterial Activity and Oral Efficacy
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Abstract
Utilizing a fully synthetic route to tetracycline analogues,
the C-9 side-chain of the fluorocyclines was optimized for both antibacterial
activity and oral efficacy. Compounds were identified that overcome
both efflux (<i>tet</i>(K), <i>tet</i>(A)) and
ribosomal protection (<i>tet</i>(M)) tetracycline-resistance
mechanisms and are active against Gram-positive and Gram-negative
organisms. A murine systemic infection model was used as an oral efficacy
screen to rapidly identify compounds with oral bioavailability. Two
compounds were identified that exhibit both oral bioavailability in
rat and clinically relevant bacterial susceptibility profiles against
major respiratory pathogens. One compound demonstrated oral efficacy
in rodent lung infection models that was comparable to marketed antibacterial
agents