Janssen Pharmaceutica Nv

Richard Scott Alexander

Kristi A Leonard

Cynthia M Milligan

Frank A Lewandowski

Diane M Maguire

Celine Schalk-Hihi

Tianbao Lu

Aihua Wang

Maxwell David Cummings

Thomas P Markotan

Dana L Johnson

Roger Francis Bone

Robert W Tuman

Brett A Tounge

Joseph Kent Barbay

Barry A Springer

Kenneth Rhodes

Lawrence C Kuo

Matthew J Todd

Robert Scannevin

John Curtis Spurlino

Paul F Jackson

Richard William Connors

Jan L Sechler

Bruce L Grasberger

Ingrid Christa Deckman

Robert A Galemmo

Anna C Maroney

Jeremy Mark Travins

Heather Rae Hufnagel

Ehab Khalil

Carsten Schubert

Carl L Manthey

Beverley Moore

Carl Crysler

Barry Springer

Robert H Scannevin

Kenneth J Rhodes

Frank A Lewandoswki

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

A number of soluble engineered forms of MGLL that are suitable for high-throughput screening and protein crystallization, as well as a crystallized form of monoacylglycerol lipase protein (MGLL) and descriptions of the X-ray diffraction patterns are disclosed. The engineered constructs of MGLL permit the expression and purification of protein suitable for crystallography or high-throughput screening and identification of ligands, which can function as active agents to MGLL. The X-ray diffraction patterns allow the three dimensional structure of MGLL to be determined at atomic resolution so that ligand binding sites on MGLL can be identified and the interactions of ligands with MGLL 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 MGLL.

Protein engineering of monoacylglycerol lipase (MGLL)

The invention is directed to triazolopyridazine compounds of Formula I: where R, R, R, R, R, and A are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of c-Met, and the use of such compounds to reduce or inhibit kinase activity of c-Met in a cell or a subject, and modulate c-Met expression in a cell or subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to c-Met. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.

Triazolopyridazine compounds

Crystal structure of monoacylglycerol lipase (MGLL)

A number of soluble engineered forms of MGLL that are suitable for high-throughput screening and protein crystallization, as well as a crystallized forms of monoacylglycerol lipase protein (MGLL) and descriptions of the X-ray diffraction patterns are disclosed. The engineered constructs of MGLL permit the expression and purification of protein suitable for crystallography or high-throughput screening and identification of ligands, which can function as active agents to MGLL. The X-ray diffraction patterns allow the three dimensional structure of MGLL to be determined at atomic resolution so that ligand binding sites on MGLL can be identified and the interactions of ligands with MGLL 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 MGLL.

Alternative crystal form of monoacylglycerol lipase (MGLL)

Triazolopyridazines as kinase modulators

The invention is directed to acylhydrazones compounds of Formula I: where R, Rand A are as defined herein, the use of such compounds as protein tyrosine kinase modulators, particularly inhibitors of c-Met, and the use of such compounds to reduce or inhibit kinase activity of c-Met in a cell or a subject, and modulate c-Met expression in a cell or subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to c-Met. The present invention is further directed to pharmaceutical compositions comprising the compounds of the present invention and to methods for treating conditions such as cancers and other cell proliferative disorders.

Acylhydrazones as kinase modulators

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Newark, DE, United States of America

Richard Scott Alexander