Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes.
A systematic study of P2 and P3 substitution in a series of vinyl sulfone cysteine protease inhibitors is described. The introduction of a methyl substituent in the P2 phenylalanine aryl ring had a favorable effect on protease inhibition and conferred modest selectivity for rhodesain over cruzain. Rhodesain selectivity could be enhanced further by combining these P2 modifications with certain P3 amide substituents.
Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA.
Priyadarshini
P
Jaishankar
Elizabeth
E
Hansell
Dong-Mei
DM
Zhao
Patricia S
PS
Doyle
James H
JH
McKerrow
Adam R
AR
Renslo
D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005030:Ethylenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects* / Q000201:enzymology
D015853:Cysteine Proteinase Inhibitors; D005030:Ethylenes; D013451:Sulfonic Acids; D014344:Trypanocidal Agents; C085726:ethylenesulfonic acid