3SFI

Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.

3SFI の概要

• エントリーDOI: 10.2210/pdb3sfi/pdb
• 関連するPDBエントリー: 1U9N 3G1L 3G1M 3O8G 3O8H
• 分子名称: Transcriptional regulatory repressor protein (TETR-family), 5,5,5-trifluoro-1-{4-[3-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}pentan-1-one (3 entities in total)
• 機能のキーワード: tetr-family, transcritptional regulatory repressor, inhibitor, dna, dna binding protein, transcription repressor-inhibitor complex, transcription repressor/inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26327.46

構造登録者

Flipo, M.,Desroses, M.,Lecat-Guillet, N.,Villemagne, B.,Blondiaux, N.,Leroux, F.,Piveteau, C.,Mathys, V.,Flament, M.P.,Siepmann, J.,Villeret, V.,Wohlkonig, A.,Wintjens, R.,Soror, S.H.,Christophe, T.,Jeon, H.K.,Locht, C.,Brodin, P.,D prez, B.,Baulard, A.R.,Willand, N. (登録日: 2011-06-13, 公開日: 2011-12-07, 最終更新日: 2023-09-13)

主引用文献

Flipo, M.,Desroses, M.,Lecat-Guillet, N.,Villemagne, B.,Blondiaux, N.,Leroux, F.,Piveteau, C.,Mathys, V.,Flament, M.P.,Siepmann, J.,Villeret, V.,Wohlkonig, A.,Wintjens, R.,Soror, S.H.,Christophe, T.,Jeon, H.K.,Locht, C.,Brodin, P.,Deprez, B.,Baulard, A.R.,Willand, N.
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 Inhibitors.
J.Med.Chem., 55:68-83, 2012

PubMed Abstract: 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.

PubMed: 22098589
DOI: 10.1021/jm200825u

実験手法

X-RAY DIFFRACTION (2.31 Å)