title: MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 3: Optimization of potency in the pyridopyrimidine series through the application of a pharmacophore model.
abstract: The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.
authors.affiliation: Daiichi Pharmaceutical Co., Ltd, 1-16-13, 134-8630, Kitakasai, Edogawa, Tokyo, Japan. nakaygoi@daiichipharm.co.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Haruko
authors.initials: H
authors.lastname: Kawato
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.forename: Masami
authors.initials: M
authors.lastname: Ohtsuka
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yokomizo
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Kuru
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ohta
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Kumi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ishida
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.forename: Monica H
authors.initials: MH
authors.lastname: Palme
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: D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000502:physiology*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; C118598:MexA protein, Pseudomonas aeruginosa; C118597:MexB protein, Pseudomonas aeruginosa; C402263:OprM protein, Pseudomonas aeruginosa; D011743:Pyrimidines