title: A Divergent SAR Study Allows Optimization of a Potent 5-HT2c Inhibitor to a Promising Antimalarial Scaffold.
abstract: 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.
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Calderón
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Vidal-Mas
authors.affiliation: Medicines for Malaria Venture (MMV) , 20, route de Pré-Bois-PO Box 1826, 1215 Geneva 15, Switzerland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Burrows
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Rosa
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mulet
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Prats
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Solana
authors.affiliation: Medicines for Malaria Venture (MMV) , 20, route de Pré-Bois-PO Box 1826, 1215 Geneva 15, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Witty
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa, 2. 28760 Tres Cantos, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
keywords: Tres Cantos Antimalarial set; divergent SAR; indoline; malaria; open-innovation