title: MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: achieving activity in vivo through the use of alternative scaffolds.
abstract: Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.
authors: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa, Tokyo 134-8630, Japan. nakagoi@daiichipharm.co.jp
authors: Kiyoshi
authors: K
authors: Nakayama
authors: Yohei
authors: Y
authors: Ishida
authors: Masami
authors: M
authors: Ohtsuka
authors: Haruko
authors: H
authors: Kawato
authors: Ken-ichi
authors: K
authors: Yoshida
authors: Yoshihiro
authors: Y
authors: Yokomizo
authors: Toshiharu
authors: T
authors: Ohta
authors: Kazuki
authors: K
authors: Hoshino
authors: Tsuyoshi
authors: T
authors: Otani
authors: Yuichi
authors: Y
authors: Kurosaka
authors: Kumi
authors: K
authors: Yoshida
authors: Hiroko
authors: H
authors: Ishida
authors: Ving J
authors: VJ
authors: Lee
authors: Thomas E
authors: TE
authors: Renau
authors: William J
authors: WJ
authors: Watkins
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D001693:Biological Transport, Active / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D024841:Fluoroquinolones / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D007769:Lactams / Q000378:metabolism; D064704:Levofloxacin; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy; D015242:Ofloxacin / Q000494:pharmacology; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D018805:Sepsis / Q000188:drug therapy; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D024841:Fluoroquinolones; D007769:Lactams; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D012709:Serum Albumin; D064704:Levofloxacin; C076246:sitafloxacin; D015242:Ofloxacin