Janssen Pharmaceutica Nv

Ortho-mcneil Pharmaceutical Corp.

3-dimensional Pharmaceuticals, Inc.

Dimensional Pharmaceuticals, Inc.

John Curtis Spurlino

Aihua Wang

Roger Francis Bone

Tianbao Lu

Richard M Soll

Bruce Edward Tomczuk

Ingrid Christa Deckman

Kristi A Leonard

Brett A Tounge

Joseph Kent Barbay

Barry A Springer

Kenneth Rhodes

Lawrence C Kuo

Frank A Lewandowski

Cynthia M Milligan

Matthew J Todd

Richard Scott Alexander

Robert Scannevin

Paul F Jackson

Diane M Maguire

Celine Schalk-Hihi

Carl L Manthey

Carsten Schubert

Bruce L Grasberger

Beverley Moore

Diane Maguire

Carl Crysler

Francis A Lewandowski

Joseph D Kwasnoski

Barry Springer

Robert H Scannevin

Kenneth J Rhodes

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.

Methods of treatment using allosteric processing inhibitors for matrix metalloproteinases

Methods for designing, selecting and/or optimizing allosteric processing inhibitors for matrix metalloproteinases

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

The present invention includes crystallized HDM2 peptides as well as descriptions of the X-ray diffraction patterns of the crystals. The diffraction patterns allow the three dimensional structure of HDM2 to be determined at atomic resolution so that ligand binding sites on HDM2 can be identified and the interactions of ligands with HDM2 amino acid residues can be modeled. Models prepared using such maps permit the design of ligands which can function as active agents which include, but are not limited to, those that function as inhibitors of MDM2 and HDM2 oncoproteins.

HDM2-inhibitor complexes and uses thereof

Cyclic oxyguanidine pyrazinone compounds are described, including compounds of the Formula I:wherein R, R, R, W, and A are as set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. Compositions for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation are described. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

Cyclic oxyguanidine pyrazinones as protease inhibitors

Cyclic oxyguanidine protease inhibitors

Described are compounds of the Formula VII:

Heterocyclic protease inhibitors

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Downingtown, PA, United States of America

John Curtis Spurlino