Abstract
A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.
Publication types
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
ADAM Proteins / antagonists & inhibitors*
-
ADAMTS4 Protein
-
ADAMTS5 Protein
-
Animals
-
Benzofurans / chemistry
-
Benzofurans / pharmacology*
-
Cells, Cultured
-
Crystallography, X-Ray
-
Hydantoins / chemistry
-
Hydantoins / pharmacology*
-
Male
-
Menisci, Tibial / drug effects
-
Menisci, Tibial / pathology
-
Microsomes / drug effects
-
Microsomes / metabolism
-
Models, Anatomic
-
Models, Molecular
-
Molecular Structure
-
Osteoarthritis / drug therapy*
-
Osteoarthritis / pathology
-
Procollagen N-Endopeptidase / antagonists & inhibitors*
-
Protease Inhibitors / chemistry
-
Protease Inhibitors / pharmacology*
-
Rats
-
Rats, Inbred Lew
-
Structure-Activity Relationship
-
Tibial Meniscus Injuries
Substances
-
Benzofurans
-
Hydantoins
-
N-((4-(1-methylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide
-
Protease Inhibitors
-
ADAM Proteins
-
ADAMTS5 Protein
-
Adamts5 protein, rat
-
Procollagen N-Endopeptidase
-
ADAMTS4 Protein
Associated data
-
PDB/4KW7
-
PDB/4KWE
-
PDB/4KWI