title: Synthesis of macrocyclic trypanosomal cysteine protease inhibitors.
abstract: The importance of cysteine proteases in parasites, compounded with the lack of redundancy compared to their mammalian hosts makes proteases attractive targets for the development of new therapeutic agents. The binding mode of K11002 to cruzain, the major cysteine protease of Trypanosoma cruzi was used in the design of conformationally constrained inhibitors. Vinyl sulfone-containing macrocycles were synthesized via olefin ring-closing metathesis and evaluated against cruzain and the closely related cysteine protease, rhodesain.
authors.affiliation: Department of Chemistry, Scripps Florida, 5353 Parkside Drive, RE-2, Jupiter, FL 33458, USA.
authors.forename: Yen Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lira
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000201:enzymology*; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D010879:Piperazines; D015800:Protozoan Proteins; D013450:Sulfones; D014105:Tosyl Compounds; D014344:Trypanocidal Agents; D014753:Vinyl Compounds; C115125:morpholin- urea-phenylalanyl-homophenylalanyl-vinylsulfone-phenyl; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C446033:rhodesain