rs-130830 has been researched along with Osteoarthritis* in 3 studies
3 other study(ies) available for rs-130830 and Osteoarthritis
| Article | Year |
|---|---|
Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.
Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data. Topics: Animals; Benzoates; Binding Sites; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Osteoarthritis; Quinazolines; Rats; Structure-Activity Relationship | 2014 |
Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13).
Computer aided drug design led to a new class of spiro-barbiturates (e.g., 4a, MMP-13 K(i)=4.7 nM) that are potent inhibitors of MMP-13. Topics: Barbiturates; Computer Simulation; Computer-Aided Design; Drug Design; Enzyme Inhibitors; Humans; Kinetics; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Models, Molecular; Osteoarthritis; Spiro Compounds; Structure-Activity Relationship | 2005 |
Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis.
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described. Topics: ADAM Proteins; ADAM17 Protein; Administration, Oral; Animals; Binding Sites; Biological Assay; Cartilage; Cattle; Crystallography, X-Ray; Dialysis; Dogs; Haplorhini; Humans; Hydroxamic Acids; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloendopeptidases; Mice; Models, Molecular; Osteoarthritis; Piperidines; Protease Inhibitors; Rabbits; Rats; Structure-Activity Relationship; Sulfones | 2003 |