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ACS Med Chem Lett. 2012 Feb 9;3(5):373-7. doi: 10.1021/ml300008j. eCollection 2012 May 10.

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

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Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
Medicines for Malaria Venture (MMV) , 20, route de Pré-Bois-PO Box 1826, 1215 Geneva 15, Switzerland.


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.


Tres Cantos Antimalarial set; divergent SAR; indoline; malaria; open-innovation

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