Document Detail


Comparison of the pharmacology of hydroxamate- and carboxylate-based matrix metalloproteinase inhibitors (MMPIs) for the treatment of osteoarthritis.
MedLine Citation:
PMID:  16612565     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE AND DESIGN: Hydroxamic-and carboxylic-acid based matrix metalloproteinase inhibitors (MMPIs) were compared for their potency against various MMPs, pharmacodynamic properties and in vivo efficacy in a model of cartilage degeneration. MATERIALS AND METHODS: The MMPIs were evaluated for their ability to inhibit human MMPs using the quenched fluorescence assay. The ability of the MMPIs to inhibit the degeneration of the knee joint was evaluated in rats injected intraarticularly with iodoacetate. The amount of MMPI in the plasma and cartilage was determined using liquid chromatography/mass spectrometry/mass spectrometry (LC/ MS/MS). Plasma protein binding was measured by ultrafiltration and unbound MMPI was quantitated using HPLC. RESULTS: The hydroxamic acid based inhibitor PGE-3321996 and the carboxylic acids PGE-2909492 and PGE-6292544 were potent MMP-13 inhibitors, but only the hydroxamic acid PGE 3321996 demonstrated significant inhibition of knee degeneration in the rat iodoacetate model. Both of the carboxylic acids demonstrated superior pharmacokinetic properties and established much higher plasma concentrations than the hydroxamic acid. However, neither of the carboxylic acids was detectable in the cartilage, whereas, the hydroxamic acid was present in both the cartilage and the plasma. The carboxylic acid based MMPIs also demonstrated higher plasma protein binding (>99%) than the hydroxamic acid (79%). CONCLUSIONS: Carboxylic acid-based MMPIs were identified that had superior in vivo plasma exposure compared to a hydroxamic acid inhibitor but lacked in vivo efficacy in the rat iodoacetate model of cartilage degeneration. The lack of in vivo efficacy of the carboxylic acid based MMPIs were probably due to their lack of cartilage penetration which was related to their physicochemical properties.
Authors:
M J Janusz; E B Hookfin; K K Brown; L C Hsieh; S A Heitmeyer; Y O Taiwo; M G Natchus; S Pikul; N G Almstead; B De; S X Peng; T R Baker; V Patel
Related Documents :
24201025 - Open fermentative production of l-lactic acid with high optical purity by thermophilic ...
3517135 - Demonstration of carboxyl and thiol protease activities in adult schistosoma mansoni, d...
23564035 - Physicochemical surface properties of cupriavidus metallidurans ch34 and pseudomonas pu...
19360935 - Adsorption of c4-dicarboxylic acids at the hematite/water interface.
1499775 - The evaluation in the ames test of the mutagenicity of tetrahydro-beta-carboline-3-carb...
8784005 - Myocardial substrate oxidation during warm continuous blood cardioplegia.
Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Inflammation research : official journal of the European Histamine Research Society ... [et al.]     Volume:  55     ISSN:  1023-3830     ISO Abbreviation:  Inflamm. Res.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-04-13     Completed Date:  2006-06-23     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9508160     Medline TA:  Inflamm Res     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  60-5     Citation Subset:  IM    
Affiliation:
Procter & Gamble Pharmaceuticals Inc., 8700 Mason-Montgomery Rd., Mailbox 1069, Mason, OH 45040-9462, USA. Janusz.mj@pg.com
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry,  pharmacokinetics*,  therapeutic use*
Animals
Carboxylic Acids* / chemistry,  pharmacokinetics,  therapeutic use
Cartilage / chemistry,  pathology
Disease Models, Animal
Humans
Hydroxamic Acids / chemistry,  pharmacokinetics*,  therapeutic use*
Iodoacetates / toxicity
Knee Joint / pathology
Male
Matrix Metalloproteinases / antagonists & inhibitors*
Molecular Structure
Osteoarthritis / chemically induced,  drug therapy*,  pathology
Phenylalanine / analogs & derivatives*,  chemistry,  pharmacokinetics,  therapeutic use
Plasma / chemistry
Protease Inhibitors* / chemistry,  pharmacokinetics,  therapeutic use
Rats
Rats, Sprague-Dawley
Sulfonamides / chemistry,  pharmacokinetics*,  therapeutic use*
Sulfones / chemistry,  pharmacokinetics*,  therapeutic use*
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Carboxylic Acids; 0/Hydroxamic Acids; 0/Iodoacetates; 0/PGE 2909492; 0/PGE 3321996; 0/PGE 6292544; 0/Protease Inhibitors; 0/Sulfonamides; 0/Sulfones; 63-91-2/Phenylalanine; EC 3.4.24.-/Matrix Metalloproteinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to ...
Next Document:  Release and permeation of histamine in isolated caecum epithelia of pigs.