<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Flipo,M.</style></author><author><style face="normal" font="default" size="100%">Desroses,M.</style></author><author><style face="normal" font="default" size="100%">Lecat-Guillet,N.</style></author><author><style face="normal" font="default" size="100%">Villemagne,B.</style></author><author><style face="normal" font="default" size="100%">Blondiaux,N.</style></author><author><style face="normal" font="default" size="100%">Leroux,F.</style></author><author><style face="normal" font="default" size="100%">Piveteau,C.</style></author><author><style face="normal" font="default" size="100%">Vanessa Mathys</style></author><author><style face="normal" font="default" size="100%">Flament,M.P.</style></author><author><style face="normal" font="default" size="100%">Siepmann,J.</style></author><author><style face="normal" font="default" size="100%">Villeret,V.</style></author><author><style face="normal" font="default" size="100%">Wohlkonig,A.</style></author><author><style face="normal" font="default" size="100%">Wintjens,R.</style></author><author><style face="normal" font="default" size="100%">Soror,S.H.</style></author><author><style face="normal" font="default" size="100%">Christophe,T.</style></author><author><style face="normal" font="default" size="100%">Jeon,H.K.</style></author><author><style face="normal" font="default" size="100%">Locht,C.</style></author><author><style face="normal" font="default" size="100%">Brodin,P.</style></author><author><style face="normal" font="default" size="100%">Deprez,B.</style></author><author><style face="normal" font="default" size="100%">Baulard,A.R.</style></author><author><style face="normal" font="default" size="100%">Willand,N.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Ethionamide boosters. 2. Combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1,2,4-oxadiazole EthR inhibitors31058</style></title><secondary-title><style face="normal" font="default" size="100%">J.Med.Chem.</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">0</style></keyword><keyword><style  face="normal" font="default" size="100%">a</style></keyword><keyword><style  face="normal" font="default" size="100%">Administration,Oral</style></keyword><keyword><style  face="normal" font="default" size="100%">Agent</style></keyword><keyword><style  face="normal" font="default" size="100%">Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">antagonists &amp; inhibitors</style></keyword><keyword><style  face="normal" font="default" size="100%">Antibiotic</style></keyword><keyword><style  face="normal" font="default" size="100%">Antitubercular Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">article</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Line</style></keyword><keyword><style  face="normal" font="default" size="100%">chemical synthesis</style></keyword><keyword><style  face="normal" font="default" size="100%">chemistry</style></keyword><keyword><style  face="normal" font="default" size="100%">Combination</style></keyword><keyword><style  face="normal" font="default" size="100%">Control</style></keyword><keyword><style  face="normal" font="default" size="100%">Crystallography,X-Ray</style></keyword><keyword><style  face="normal" font="default" size="100%">de</style></keyword><keyword><style  face="normal" font="default" size="100%">Design</style></keyword><keyword><style  face="normal" font="default" size="100%">DRUG</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Design</style></keyword><keyword><style  face="normal" font="default" size="100%">drug effects</style></keyword><keyword><style  face="normal" font="default" size="100%">Drug Synergism</style></keyword><keyword><style  face="normal" font="default" size="100%">electronic</style></keyword><keyword><style  face="normal" font="default" size="100%">Ethionamide</style></keyword><keyword><style  face="normal" font="default" size="100%">EVALUATION</style></keyword><keyword><style  face="normal" font="default" size="100%">exposure</style></keyword><keyword><style  face="normal" font="default" size="100%">expression</style></keyword><keyword><style  face="normal" font="default" size="100%">France</style></keyword><keyword><style  face="normal" font="default" size="100%">Human</style></keyword><keyword><style  face="normal" font="default" size="100%">im</style></keyword><keyword><style  face="normal" font="default" size="100%">IS</style></keyword><keyword><style  face="normal" font="default" size="100%">journal</style></keyword><keyword><style  face="normal" font="default" size="100%">Macrophages</style></keyword><keyword><style  face="normal" font="default" size="100%">metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">mice</style></keyword><keyword><style  face="normal" font="default" size="100%">microbiology</style></keyword><keyword><style  face="normal" font="default" size="100%">Microsomes,Liver</style></keyword><keyword><style  face="normal" font="default" size="100%">Models,Molecular</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium</style></keyword><keyword><style  face="normal" font="default" size="100%">Mycobacterium tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">ON</style></keyword><keyword><style  face="normal" font="default" size="100%">Oxadiazoles</style></keyword><keyword><style  face="normal" font="default" size="100%">pathogen</style></keyword><keyword><style  face="normal" font="default" size="100%">Pharmacokinetic</style></keyword><keyword><style  face="normal" font="default" size="100%">pharmacokinetics</style></keyword><keyword><style  face="normal" font="default" size="100%">Piperidines</style></keyword><keyword><style  face="normal" font="default" size="100%">PROCESSES</style></keyword><keyword><style  face="normal" font="default" size="100%">Prodrugs</style></keyword><keyword><style  face="normal" font="default" size="100%">protein</style></keyword><keyword><style  face="normal" font="default" size="100%">Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Repressor Proteins</style></keyword><keyword><style  face="normal" font="default" size="100%">Research</style></keyword><keyword><style  face="normal" font="default" size="100%">Research Support</style></keyword><keyword><style  face="normal" font="default" size="100%">SB - IM</style></keyword><keyword><style  face="normal" font="default" size="100%">SENSITIVITY</style></keyword><keyword><style  face="normal" font="default" size="100%">series</style></keyword><keyword><style  face="normal" font="default" size="100%">stability</style></keyword><keyword><style  face="normal" font="default" size="100%">Stereoisomerism</style></keyword><keyword><style  face="normal" font="default" size="100%">Structure-Activity Relationship</style></keyword><keyword><style  face="normal" font="default" size="100%">study</style></keyword><keyword><style  face="normal" font="default" size="100%">Tuberculosis</style></keyword><keyword><style  face="normal" font="default" size="100%">work</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2012</style></year><pub-dates><date><style  face="normal" font="default" size="100%">12/1/2012</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">83</style></number><volume><style face="normal" font="default" size="100%">55</style></volume><pages><style face="normal" font="default" size="100%">68 - 83</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration</style></abstract><issue><style face="normal" font="default" size="100%">1</style></issue><custom1><style face="normal" font="default" size="100%">38193</style></custom1><section><style face="normal" font="default" size="100%">68</style></section></record></records></xml>