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

  • Bioorg Med Chem. 2007 Nov 15;15(22):7087-97. doi: 10.1016/j.bmc.2007.07.039.
Ken-Ichi Yoshida  1 ,  Kiyoshi Nakayama ,  Masami Ohtsuka ,  Noriko Kuru ,  Yoshihiro Yokomizo ,  Atsunobu Sakamoto ,  Makoto Takemura ,  Kazuki Hoshino ,  Hiroko Kanda ,  Hironobu Nitanai ,  Kenji Namba ,  Kumi Yoshida ,  Yuichiro Imamura ,  Jason Z Zhang ,  Ving J Lee ,  William J Watkins
Affiliations
  • 1. Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd, 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. [email protected]
PMID: 17869116 DOI: 10.1016/j.bmc.2007.07.039
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.

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