Falcipain Inhibitors: Optimization Studies of the 2-Pyrimidinecarbonitrile Lead Series

被引:92
作者
Coteron, Jose M. [2 ]
Catterick, David [4 ]
Castro, Julia [2 ]
Chaparro, Maria J. [2 ]
Diaz, Beatriz [2 ]
Fernandez, Esther [2 ]
Ferrer, Santiago [3 ]
Gamo, Francisco J. [3 ]
Gordo, Mariola [2 ]
Gut, Jiri [1 ]
de las Heras, Laura [2 ]
Legac, Jennifer [1 ]
Marco, Maria [2 ]
Miguel, Juan [2 ]
Munoz, Vicente [2 ]
Porras, Esther [2 ]
de la Rosa, Juan C. [2 ]
Ruiz, Jose R. [2 ]
Sandoval, Elena [2 ]
Ventosa, Pilar [2 ]
Rosenthal, Philip J. [1 ]
Fiandor, Jose M. [2 ]
机构
[1] Univ Calif San Francisco, Dept Med, San Francisco Gen Hosp, San Francisco, CA 94143 USA
[2] GlaxoSmithKline, Dept Drug Discovery Chem, Madrid 28760, Spain
[3] GlaxoSmithKline, Dept Drug Discovery Biol, DDW, Madrid 28760, Spain
[4] GlaxoSmithKline, Synthet Chem, Tonbridge TN11 9AN, Kent, England
关键词
PLASMODIUM-FALCIPARUM; CYSTEINE PROTEASE; MALARIA; EXPRESSION; BINDING; PROTEINASE; NITRILES; POTENT;
D O I
10.1021/jm100556b
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
引用
收藏
页码:6129 / 6152
页数:24
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