A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold

被引：17

作者：

Calderon, Felix ^{[1
]}

Vidal-Mas, Jaume ^{[1
]}

Burrows, Jeremy ^{[2
]}

de la Rosa, Juan Carlos ^{[1
]}

Jimenez-Diaz, Maria Belen ^{[1
]}

Mulet, Teresa ^{[1
]}

Prats, Sara ^{[1
]}

Solana, Jorge ^{[1
]}

Witty, Michael ^{[2
]}

Gamo, Francisco Javier ^{[1
]}

Fernandez, Esther ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, DDW, Madrid 28760, Spain

[2] MMV, CH-1215 Geneva 15, Switzerland

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 05期

关键词：

indoline; malaria; Tres Cantos Antimalarial set; divergent SAR; open-innovation; CYCLOPROPYL CARBOXAMIDES; STARTING POINTS; DRUG DISCOVERY; RECEPTORS; IDENTIFICATION; CHALLENGES; BLOCKADE; SCREEN; AGENTS; TCAMS;

D O I：

10.1021/ml300008j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

From the 13 533 chemical structures published by GlaxoSmithKline in 2010, we identified 47 quality starting points for lead optimization. One of the most promising hits was the TCMDC-139046, a molecule presenting an indoline core, which is well-known for its anxiolytic properties by interacting with serotonin antagonist receptors 5-HT2. The inhibition of this target will complicate the clinical development of these compounds as antimalarials. Herein, we present the antimalarial profile of this series and our efforts to avoid interaction with this receptor, while maintaining a good antiparasitic potency. By using a double-divergent structure-activity relationship analysis, we have obtained a novel lead compound harboring an indoline core.

引用

页码：373 / 377

页数：5

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