A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold
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- 作者：F茅lix Calder贸n ; Jaume Vidal-Mas ; Jeremy Burrows ; Juan Carlos de la Rosa ; Mar铆a Bel茅n Jim茅nez-D铆az ; Teresa Mulet ; Sara Prats ; Jorge Solana ; Michael Witty ; Francisco Javier Gamo ; Esther Fern谩ndez
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：May 10, 2012
- 年：2012
- 卷：3
- 期：5
- 页码：373-377
- 全文大小：320K
- 年卷期：v.3,no.5(May 10, 2012)
- ISSN：1948-5875
文摘
From the 13鈥?33 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鈥揳ctivity relationship analysis, we have obtained a novel lead compound harboring an indoline core.