5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (aggrecanase-2)

5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (aggrecanase-2)

5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2007-10, Vol.17 (20), p.5630-5633
Hauptverfasser: Bursavich, Matthew G, Gilbert, Adam M, Lombardi, Sabrina, Georgiadis, Katy E, Reifenberg, Erica, Flannery, Carl R, Morris, Elisabeth A
Format: Artikel
Sprache:eng
Schlagworte:
Endopeptidases - metabolism
Indoles - chemistry
Molecular Structure
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Structure-Activity Relationship
Thiadiazoles - chemical synthesis
Thiadiazoles - chemistry
Thiadiazoles - pharmacology
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Zusammenfassung:5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
ISSN:0960-894X
DOI:10.1016/j.bmcl.2007.07.048