Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials

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• 作者：Matthew McConville ; Jorge Fern谩ndez ; 脥帽igo Angulo-Barturen ; Noemi Bahamontes-Rosa ; Lluis Ballell-Pages ; Pablo Casta帽eda ; Cristina de C贸zar ; Benigno Crespo ; Laura Guijarro ; Mar铆a Bel茅n Jim茅nez-D铆az ; Maria S. Mart铆nez-Mart铆nez ; Jaime de Mercado ; 脕ngel Santos-Villarejo ; Laura M. Sanz ; Micol Frigerio ; Gina Washbourn ; Stephen A. Ward ; Gemma L. Nixon ; Giancarlo A. Biagini ; Neil G. Berry ; Michael J. Blackman ; F茅lix Calder贸n ; Paul M. O鈥橬eill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 27, 2015
• 年：2015
• 卷：58
• 期：16
• 页码：6448-6455
• 全文大小：456K
• ISSN：1520-4804

文摘

Screening of the GSK corporate collection, some 1.9 million compounds, against <i>Plasmodium falciparumi> (<i>Pfi>), 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 <i>Pfi> infection with an ED₅₀ of 100 and ED₉₀ of between 100 and 150 mg kgp>鈭?p>, respectively. The results presented encourage further investigations to identify the target of these highly active compounds.