Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes

Priyadarshini Jaishankar; Elizabeth Hansell; Dong-Mei Zhao; Patricia S Doyle; James H McKerrow; Adam R Renslo

doi:10.1016/j.bmcl.2007.11.070

Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes

Bioorg Med Chem Lett. 2008 Jan 15;18(2):624-8. doi: 10.1016/j.bmcl.2007.11.070. Epub 2007 Nov 22.

Authors

Priyadarshini Jaishankar¹, Elizabeth Hansell, Dong-Mei Zhao, Patricia S Doyle, James H McKerrow, Adam R Renslo

Affiliation

¹ Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA.

PMID: 18055204
DOI: 10.1016/j.bmcl.2007.11.070

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cysteine Proteinase Inhibitors / chemistry*
Cysteine Proteinase Inhibitors / pharmacology*
Ethylenes / chemistry*
Ethylenes / pharmacology*
Structure-Activity Relationship
Sulfonic Acids / chemistry*
Sulfonic Acids / pharmacology*
Trypanocidal Agents / chemistry*
Trypanocidal Agents / pharmacology*
Trypanosoma / drug effects*
Trypanosoma / enzymology

Substances

Cysteine Proteinase Inhibitors
Ethylenes
Sulfonic Acids
Trypanocidal Agents
ethylenesulfonic acid

Grants and funding

AI35707/AI/NIAID NIH HHS/United States