title: MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate.
abstract: A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.
authors.affiliation: Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. yoshida.kenichi.rs@daiichisankyo.co.jp
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Masami
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Noriko
authors.initials: N
authors.lastname: Kuru
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yokomizo
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemura
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanda
authors.forename: Hironobu
authors.initials: H
authors.lastname: Nitanai
authors.forename: Kenji
authors.initials: K
authors.lastname: Namba
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Imamura
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Zhang
authors.forename: Ving J
authors.initials: VJ
authors.lastname: Lee
authors.forename: William J
authors.initials: WJ
authors.lastname: Watkins
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D000882:Haplorhini; D007262:Infusions, Intravenous; D008297:Male; D026901:Membrane Transport Proteins; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; C525716:D13-9001; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D010880:Piperidines; D000644:Quaternary Ammonium Compounds