title: Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy.
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 (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.
authors.affiliation: Discovery Chemistry, Tetraphase Pharmaceuticals, 480 Arsenal Street, Watertown, Massachusetts 02472, United States. rclark@tphase.com
authors.forename: Roger B
authors.initials: RB
authors.lastname: Clark
authors.forename: Diana K
authors.initials: DK
authors.lastname: Hunt
authors.forename: Minsheng
authors.initials: M
authors.lastname: He
authors.forename: Catherine
authors.initials: C
authors.lastname: Achorn
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chen
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Deng
authors.forename: Corey
authors.initials: C
authors.lastname: Fyfe
authors.forename: Trudy H
authors.initials: TH
authors.lastname: Grossman
authors.forename: Philip C
authors.initials: PC
authors.lastname: Hogan
authors.forename: William J
authors.initials: WJ
authors.lastname: O'Brien
authors.forename: Louis
authors.initials: L
authors.lastname: Plamondon
authors.forename: Magnus
authors.initials: M
authors.lastname: Rönn
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Sutcliffe
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhu
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiao
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D003520:Cyclophosphamide; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000209:etiology / Q000382:microbiology; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013753:Tetracycline Resistance; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013754:Tetracyclines; D003520:Cyclophosphamide