1610043-18-9Relevant academic research and scientific papers
MACROCYCLIC COMPOUNDS AND USES THEREOF
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Paragraph 00198; 00199, (2014/06/11)
The present invention relates to novel macrocyclic compounds of Formula I and their use as novel therapeutic agents for example as novel compounds used in methods of preventing and/or treating a disease, condition or state in a subject associated with dysregulation of protease activity and/or dysregulation of proteosome activity
Macrocyclic protease inhibitors with reduced peptide character
Chua, Krystle C. H.,Pietsch, Markus,Zhang, Xiaozhou,Hautmann, Stephanie,Chan, Hon Y.,Bruning, John B.,Guetschow, Michael,Abell, Andrew D.
, p. 7828 - 7831 (2014/08/05)
There is a real need for simple structures that define a β-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography. The incorporation of a pyrrole into a peptide backbone generates simple macrocycles that adopt a β-strand geometry. The attachment of a P1 amino aldehyde to these templates then gives rise to potent protease inhibitors (see example, top, which has Ki values of 440 pM and 920 pM against the cysteine cathepsins L and S, respectively). A crystal structure of a related derivative bound to chymotrypsin (see picture, bottom) confirms the design.
