Title:
MATRIX METALLOPROTEINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO2002064080
Kind Code:
A3
Abstract:
Compounds are provided that bind allosterically to the catalytic domain of MMP-13 and comprise a hydrophobic group, first and second hydrogen bond acceptors and at least one, and preferably both, of a third hydrogen bond acceptor and a second hydrophobic group. Cartesian coordinates for centroids of the above features are defined in the specification. When the ligand binds to MMP-13, the first, second and third (when present) hydrogen bond acceptors bond respectively with Thr245, Thr247 and Met 253, the first hydrophobic group locates within the S1' channel of MMP-13 and the second hydrophobic group (when present) is relatively open to solvent. The compounds specifically inhibit the matrix metalloproteinase-13 enzyme and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
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Inventors:
ANDRIANJARA CHARLES (FR)
ORTWINE DANIEL FRED (US)
PAVLOVSKY ALEXANDER GREGORY (US)
ROARK WILLIAM HOWARD (US)
ORTWINE DANIEL FRED (US)
PAVLOVSKY ALEXANDER GREGORY (US)
ROARK WILLIAM HOWARD (US)
Application Number:
PCT/IB2002/000447
Publication Date:
December 12, 2002
Filing Date:
February 13, 2002
Export Citation:
Assignee:
WARNER LAMBERT CO (US)
ANDRIANJARA CHARLES (FR)
ORTWINE DANIEL FRED (US)
PAVLOVSKY ALEXANDER GREGORY (US)
ROARK WILLIAM HOWARD (US)
ANDRIANJARA CHARLES (FR)
ORTWINE DANIEL FRED (US)
PAVLOVSKY ALEXANDER GREGORY (US)
ROARK WILLIAM HOWARD (US)
International Classes:
C07D239/90; A61K31/00; A61K31/36; A61K31/444; A61K31/517; A61K31/519; A61P1/02; A61P1/04; A61P9/04; A61P9/10; A61P11/00; A61P11/06; A61P17/06; A61P19/00; A61P19/02; A61P19/10; A61P21/04; A61P29/00; A61P35/00; A61P43/00; C07C69/76; C07C69/92; C07C205/57; C07C229/62; C07C235/60; C07D213/30; C07D213/40; C07D239/96; C07D285/14; C07D285/24; C07D285/32; C07D317/54; C07D317/58; C07D401/06; C07D401/12; C07D405/12; C07D405/14; C07D409/06; C07D409/12; C07D409/14; C07D417/12; C07D471/04; C07D487/04; C07D495/04; C07D513/04; (IPC1-7): A61K31/16; A61K31/36; A61K31/41; A61K31/44; A61K31/505; A61K31/517; A61K31/519; A61K31/54; A61P19/00; C07C233/00; C07D213/02; C07D239/02; C07D239/72; C07D285/14; C07D285/22; C07D317/44; C07D401/02; C07D417/02; C07D495/02
Other References:
MOY ET AL.: "High-resolution solution structures of the catalytic fragment of human collagenase-3 (MMP-13) complexed with a hydroxamic acid inhibitor", JOURNAL OF MOLECULAR BIOLOGY, vol. 302, no. 3, 22 September 2000 (2000-09-22), pages 671 - 689, XP002955937
CHEN ET AL.: "Structure-based design of a novel, potent and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 122, no. 40, 11 October 2000 (2000-10-11), pages 9648 - 9654, XP001010185
LOVEJOY ET AL.: "Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors", NATURE STRUCTURAL BIOLOGY, vol. 6, no. 3, March 1999 (1999-03-01), pages 217 - 221, XP002955938
See also references of EP 1361873A4
CHEN ET AL.: "Structure-based design of a novel, potent and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 122, no. 40, 11 October 2000 (2000-10-11), pages 9648 - 9654, XP001010185
LOVEJOY ET AL.: "Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors", NATURE STRUCTURAL BIOLOGY, vol. 6, no. 3, March 1999 (1999-03-01), pages 217 - 221, XP002955938
See also references of EP 1361873A4
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