Fluorocyclines. 2. Optimization of the C-9 Side-Chain for Antibacterial Activity and Oral Efficacy

被引：59

作者：

Clark, Roger B. ^{[1
]}

Hunt, Diana K. ^{[1
]}

He, Minsheng ^{[1
]}

Achorn, Catherine ^{[2
]}

Chen, Chi-Li ^{[1
]}

Deng, Yonghong ^{[1
]}

Fyfe, Corey ^{[2
]}

Grossman, Trudy H. ^{[2
]}

Hogan, Philip C. ^{[3
]}

O'Brien, William J. ^{[2
]}

Plamondon, Louis ^{[1
]}

Roenn, Magnus ^{[3
]}

Sutcliffe, Joyce A. ^{[2
]}

Zhu, Zhijian ^{[3
]}

Xiao, Xiao-Yi ^{[1
]}

机构：

[1] Tetraphase Pharmaceut, Discovery Chem, Watertown, MA 02472 USA

[2] Tetraphase Pharmaceut, Microbiol, Watertown, MA 02472 USA

[3] Tetraphase Pharmaceut, Proc Chem R&D, Watertown, MA 02472 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 02期

关键词：

TETRACYCLINE RESISTANCE DETERMINANTS; ACINETOBACTER-BAUMANNII; BACTERIAL-RESISTANCE; RIBOSOMAL-SUBUNIT; ANTIBIOTICS; 6-DEOXYTETRACYCLINES; GLYCYLCYCLINES; PHARMACOKINETICS; TIGECYCLINE; MINOCYCLINE;

D O I：

10.1021/jm201467r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (tet(K), tet(A)) and ribosomal protection (tet(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,

引用

页码：606 / 622

页数：17

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