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.
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.
Nakayama
Kiyoshi
K
Daiichi Pharmaceutical Co., Ltd, 1-16-13, 134-8630, Kitakasai, Edogawa, Tokyo, Japan. nakaygoi@daiichipharm.co.jp
Kawato
Haruko
H
Watanabe
Jun
J
Ohtsuka
Masami
M
Yoshida
Ken-ichi
K
Yokomizo
Yoshihiro
Y
Sakamoto
Atsunobu
A
Kuru
Noriko
N
Ohta
Toshiharu
T
Hoshino
Kazuki
K
Yoshida
Kumi
K
Ishida
Hiroko
H
Cho
Aesop
A
Palme
Monica H
MH
Zhang
Jason Z
JZ
Lee
Ving J
VJ
Watkins
William J
WJ
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
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