title: Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials.
abstract: Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al. clustered and computationally filtered the TCAMS through a variety of criteria and reported 47 series containing a total of 522 compounds. From this enhanced set, we identified the carbamoyl triazole TCMDC-134379 (1), a known serine protease inhibitor, as an excellent starting point for SAR profiling. Lead optimization of 1 led to several molecules with improved antimalarial potency, metabolic stabilities in mouse and human liver microsomes, along with acceptable cytotoxicity profiles. Analogue 44 displayed potent in vitro activity (IC50 = 10 nM) and oral activity in a SCID mouse model of Pf infection with an ED50 of 100 and ED90 of between 100 and 150 mg kg(-1), respectively. The results presented encourage further investigations to identify the target of these highly active compounds.
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Matthew
authors.initials: M
authors.lastname: McConville
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Íñigo
authors.initials: Í
authors.lastname: Angulo-Barturen
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Noemi
authors.initials: N
authors.lastname: Bahamontes-Rosa
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell-Pages
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Castañeda
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: de Cózar
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Benigno
authors.initials: B
authors.lastname: Crespo
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guijarro
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, 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, Spain.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Martínez-Martínez
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: de Mercado
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Santos-Villarejo
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Micol
authors.initials: M
authors.lastname: Frigerio
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Gina
authors.initials: G
authors.lastname: Washbourn
authors.affiliation: Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Nixon
authors.affiliation: Liverpool School of Tropical Medicine , Pembroke Place, Liverpool L3 5QA, United Kingdom.
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Neil G
authors.initials: NG
authors.lastname: Berry
authors.affiliation: Division of Parasitology, MRC National Institute for Medical Research , Mill Hill, London NW7 1AA, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Calderón
authors.affiliation: Department of Chemistry, University of Liverpool , Liverpool L69 7ZD, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy / Q000523:psychology; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D015842:Serine Proteinase Inhibitors; D014230:Triazoles