US 8,753,857 B2 · Crystal structure of the pro form of a matrix metalloproteinase and an allosteric processing inhibitor

Crystal structure of the pro form of a matrix metalloproteinase and an allosteric processing inhibitor

AssigneeJanssen Pharmaceutica NV

InventorsKristi A. Leonard, Richard Scott Alexander, Joseph Kent Barbay, Roger F. Bone, Ingrid Christa Deckman, Paul F. Jackson, Lawrence C. Kuo, Frank A. Lewandowski, Diane M. Maguire, Cynthia M. Milligan, Kenneth J. Rhodes, Robert H. Scannevin, Celine Schalk-Hihi, Barry Springer, John C. Spurlino, Matthew J. Todd, Brett A. Tounge, Aihua Wang

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Abstract

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.

Claims4

Dependent claims

A crystal comprising the pro form of a matrix metalloproteinase 9 (proMMP9), wherein the proMMP9 has the amino acid sequence comprising SEQ ID NO:

12, and wherein the crystal of the proMMP9 is in apo form or in complex with a chemical entity, wherein said chemical entity is a small-molecule allosteric processing inhibitor of the proMMP9, wherein said crystal forms in space group C2 having unit cell having dimensions selected from the group consisting of:
the unit cell dimensions of a=90.3 (Å), b=73.2 (Å), c=77.5 (Å), β=106.3°, the unit cell dimensions of a=91.7 (Å), b=73.7 (Å), c=79.4 (Å), β=105.4°, the unit cell dimensions of a=90.7 (Å), b=73.0 (Å), c=78.2 (Å), β=104.6°, the unit cell dimensions of a=91.0 (Å), b=73.6 (Å), c=78.0 (Å), β=106° and the unit cell dimensions of a=90.0 (Å), b=77.1 (Å), c=75.0 (Å), β=105°.

Dependencies are inferred from the claim text.

Facts

Application

13/533,108Filed 26 Jun 2012 · us provisional application

Priority

29 Jun 2011

Published

US 2013/0040360 A114 Feb 2013

Granted

17 Jun 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C12N 9/6491
Metalloendopeptidases: matrix metalloproteases [MMP's], e.g. interstitial collagenase ; Stromelysins ; Matrilysin
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents