Methods of treatment using allosteric processing inhibitors for matrix metalloproteinases

摘要

The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

主权项

1. A method of inhibiting activation of a pro matrix metalloprotease (proMMP) using a chemical entity selected from the group consisting of: a small-molecule allosteric processing inhibitor and solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof, wherein the small-molecule allosteric processing inhibitor comprises a compound selected from the group consisting of
Example 1: Example 2: Example 3:and
Example 4: