Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

被引：108

作者：

Encinas, Lourdes ^{[2
]}

O'Keefe, Heather ^{[1
]}

Neu, Margarete ^{[3
]}

Remuinan, Modesto J. ^{[2
]}

Patel, Amish M. ^{[1
]}

Guardia, Ana ^{[2
]}

Davie, Christopher P. ^{[1
]}

Perez-Macias, Natalia ^{[4
]}

Yang, Hongfang ^{[1
]}

Convery, Maire A. ^{[3
]}

Messer, Jeff A. ^{[1
]}

Perez-Herran, Esther ^{[2
]}

Centrella, Paolo A. ^{[5
]}

Alvarez-Gomez, Daniel ^{[2
]}

Clark, Matthew A. ^{[5
]}

Huss, Sophie ^{[2
]}

O'Donovan, Gary K. ^{[1
]}

Ortega-Muro, Fatima ^{[2
]}

McDowell, William ^{[6
]}

Castaneda, Pablo ^{[2
]}

Arico-Muendel, Christopher C. ^{[1
]}

Pajk, Stane ^{[7
]}

Rullas, Joaquin ^{[2
]}

Angulo-Barturen, Inigo ^{[2
]}

Alvarez-Ruiz, Emilio ^{[8
]}

Mendoza-Losana, Alfonso ^{[2
]}

Pages, Lluis Ballell ^{[2
]}

Castro-Pichel, Julia ^{[2
]}

Evindar, Ghotas ^{[1
]}

机构：

[1] GlaxoSmithKline, Platform Technol & Sci, ELT Boston, Waltham, MA 02451 USA

[2] GlaxoSmithKline, Dis Dev World, Madrid 28760, Spain

[3] GlaxoSmithKline, Computat & Struct Chem, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England

[4] CSIC, Inst Quim Med, E-28006 Madrid, Spain

[5] X Chem Inc, Waltham, MA 02453 USA

[6] GlaxoSmithKline, Platform Technol & Sci, Biol Reagent & Assay Dev, Stevenage SG1 2NY, Herts, England

[7] Univ Ljubljana, Fac Pharm, SI-1000 Ljubljana, Slovenia

[8] GlaxoSmithKline, Ctr Invest Basica, Madrid 28760, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 04期

关键词：

DRUG-RESISTANT TUBERCULOSIS; ENOYL-ACP REDUCTASE; CRYSTAL-STRUCTURE; TARGET; SOLUBILITY;

D O I：

10.1021/jm401326j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

引用

页码：1276 / 1288

页数：13

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