- Falcipain inhibitors: Optimization studies of the 2-pyrimidinecarbonitrile lead series
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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.
- Coterón, Jose M.,Catterick, David,Castro, Julia,Chaparro, María J.,Díaz, Beatriz,Fernández, Esther,Ferrer, Santiago,Gamo, Francisco J.,Gordo, Mariola,Gut, Jiri,De Las Heras, Laura,Legac, Jennifer,Marco, Maria,Miguel, Juan,Mu?oz, Vicente,Porras, Esther,De La Rosa, Juan C.,Ruiz, Jose R.,Sandoval, Elena,Ventosa, Pilar,Rosenthal, Philip J.,Fiandor, Jose M.
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supporting information; experimental part
p. 6129 - 6152
(2010/10/21)
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- PROCESS FOR MAKING SUBSTITUTED PIPERAZINYL COMPOUNDS
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A process for making a compound of formula (I): wherein R1 is C1 to C7 alkyl. The compounds having the formula (I) may be intermediates in a process for making dipeptide compounds, for example dipeptide nitrile compounds.
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Page/Page column 12
(2008/06/13)
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- Benzamide nitriles
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Compounds of the formula (I) wherein m, n, A, R1, R2, R3, R4, R5 and R6 are as described herein, together with methods for making the compounds and using the compounds for treatment of diseases or conditions mediated by Cathepsin K.
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- Model study for preparation of asymmetric N,N'-disubstituted piperazine library: Efficient synthesis of aryl piperazine and benzyl piperazine derivatives on the solid support
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Several classes of asymmetrical N,N'-disubstituted aryl piperazine and benzyl piperazine derivatives were successfully synthesized by the solid phase method from the same intermediate.
- Yamamoto, Yasuo,Ajito, Keiichi,Ohtsuka, Yasuo
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p. 379 - 380
(2007/10/03)
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