Onyx Therapeutics, Inc.

University of Kansas

Proteolix, Inc.

Ronald T Borchardt

John H Musser

Mark Stephen Smyth

Craig M Crews

Guy J Laidig

Barry A Bunin

Valentino J Stella

Kevin D Shenk

Binghe Wang

Teruna J Siahaan

Peggy A Radel

Sanjeev Gangwar

David R Borcherding

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include at least three peptide units, an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

Compounds for enzyme inhibition

Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsinlike activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.

Provided are cyclic prodrugs of biologically active peptides and peptide nucleic acids exhibiting improved cell membrane permeability and enzymatic stability, containing 3-(2'-hydroxy-4',6'-dimethyl phenyl)-3,3-dimethyl propionic acid and its deriveatives and acyloxyalkoxy linkers. Also provided are pharmaceutical compositions containing effective amounts of these cyclic prodrugs in combination with pharmaceutically acceptable carriers, excipients, or diluents.

Cyclic prodrugs of peptides and peptide nucleic acids having improved

Compounds of the formula (I) ##STR1## wherein X is .dbd.N-- or .dbd.CH-- and physiologically acceptable salts and solvents thereof which have antiviral activity, a process for the preparation of the compounds and intermediates thereof, pharmaceutical compositions containing the compounds and a method for inhibiting the propagation of virus using the compounds.

Nucleoside analogues having antiviral activity

Growing community of inventors

Lawrence, KS, United States of America

Ronald T Borchardt