Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.

A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates.

Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1.

The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group.

Cartilage damage after intraarticular exposure to collagenase 3.

Objective: To determine the in vivo effects of intraarticular MMP-13.

Methods: Human recombinant MMP-13 was injected intraarticularly (i.a.

Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody.

To determine whether the collagen network is compromised by collagenase during acute inflammation, a monoclonal antibody (9A4) was developed with specificity for the C-terminal neoepitope sequence generated by collagenase-cleavage of type II collagen (Gly-Pro-Pro-Gly-Pro-Gln-Gly-COOH). 9A4 was shown to detect the collagen collagenase-cleavage neoepitope with a K = 1.7 x 10(-7) M (type II) and K = 2 x 10(-6) M (type I).

Exercise protects against articular cartilage degeneration in the hamster.

Objective: It has been reported that osteoarthritis can occur in hamsters. The present study was undertaken to determine the effects of exercise on the composition of articular cartilage and synovial fluid and on the development of cartilage degeneration in these animals.

Methods: Young (2.

Limitation of activity in an acute model of arthritis: effect of drug treatment.

Objective And Design: The limitation of activity and its modification by therapy in an experimental arthritis was studied.

Subjects: Female hamsters in groups of six per treatment were used.

Treatment: An acute arthritis was induced by intraarticular injection of 0.

Determining selectivity of drugs by quantitative two-dimensional gel analysis. A study of tenidap, piroxicam, and dexamethasone.

In vitro pharmacologic measures of drug specificity are well established, i.e. drug interaction with a specific target such as an enzyme, receptor, or ion channel.

Effects of exercise on synovium and cartilage from normal and inflamed knees.

The effect of running activity on normal and inflamed knees was determined by light microscopic (LM) and scanning electron microscopic (SEM) observations on hamster articular cartilage. Animals were split into two groups; one housed in standard cages and one given free access to running wheels. Twenty-one days prior to analysis, half of each group was given an intra-articular injection of lipopolysaccharide (LPS) to cause an inflammation, the other half were uninjected.

Comparison of mobility changes with histological and biochemical changes during lipopolysaccharide-induced arthritis in the hamster.

Arthritis refers to a heterogeneous class of diseases characterized by impairment of movement. Yet animal models of arthritis have traditionally been based on the utilization of animals housed without the capability of extended free movement and without adjunctive measurement of mobility. To define the determinants of mobility impairment, we have established a lipopolysaccharide (LPS)-induced arthritis model in the hamster that prominently features monitoring of mobility and compares mobility changes with histological and biochemical changes during arthritis.

Changes in Mobility of the Golden Hamster with Induction of an IL-1-Induced Arthritis.

Many studies in animals have examined biochemical, immune and histological changes during arthritis; however, the study of the effects of arthritis on mobility has been largely neglected. Interleukin-1, administered by the intraarticular route into hamster knee joints, resulted in inhibition of spontaneous wheel running activity; however, the effect was transient, lasting only through the evening following IL-1 administration. A further injection of IL-1 2 days later showed still greater inhibition of running.

Some factors affecting inhibition and restoration of mobility after induction of an acute arthritis in the hamster.

Mobility is impaired during arthritis. In order to study the causes of the mobility impairment, we have examined hamsters with a LPS arthritis in which running is inhibited over a 4-5 day period. Parameters have been examined to determine which correlate with running impairment.

The effect of interleukin-1 on adhesion formation in the rat.

The potential role of interleukin-1 in postoperative adhesion formation was examined. Cecal abrasion gave a consistently higher adhesion score when compared with sham laparotomy, on the basis of adhesion number, density, and vascularity, and so was chosen for use in further studies. The extent of serosal bleeding during cecal abrasion did not affect adhesion scores.

Inhibition of interleukin 1 synthesis by tenidap: a new drug for arthritis.

Tenidap is a new antiarthritic drug of novel chemical structure. This study shows the effects of tenidap on the in vitro synthesis of interleukin 1 (IL-1). IL-1 production by murine peritoneal macrophages was induced either by stimulation with lipopolysaccharide (LPS) or by phagocytosis of zymosan.

Cyclophosphamide and 15(S)-15 methyl PGE1 correct the T/B lymphocyte ratios of NZB/NZW mice.

The lupus of NZB/NZW F1 female mice is associated with immune complex glomerulonephritis and premature death. Cyclophosphamide and 15(S)-15 methyl PGE1 therapy halt disease progression. Fluorescein conjugated antibodies were utilized to label specific leukocytes and the subsets were quantitated using a Fluorescence Activated Cell Sorter.

Effects of dazmegrel, piroxicam and cyclophosphamide on the NZB/W model of SLE.

To investigate the potential importance of prostaglandins and thromboxane in systemic lupus erythematosus (SLE), the effects of a nonsteroidal antiinflammatory drug (piroxicam) and a thromboxane synthetase inhibitor (dazmegrel) were examined on survival, proteinuria, food consumption, body weight, and peripheral lymphocyte subset distribution in the NZB/W model of autoimmune lupus disease. The effect of an immunosuppressant (cyclophosphamide) known to be effective in the treatment of murine lupus on these parameters was also examined. Cyclophosphamide at 25 mg/kg ip weekly prolonged survival, inhibited proteinuria and prevented the characteristic decline in peripheral T cells and the relative increase in B cells seen in NZB/W lupus disease while having no apparent effect on body weight or food consumption.

A pharmacologic study of the relationship between lymphocyte function and surface antigen expression.

The relationship between functional activity and distribution of lymphocyte surface markers has not been clearly defined. We have examined the relationship between cell surface markers and function under the influence of immunosuppressant therapy. We found that after immunization with EL4 cells, the development of the immune response in the BALB/c mouse was accompanied by a decrease in spleen cells which stained brightly with fluorescein-labeled monoclonal anti-Thy 1 and an increase in cells which stained with rabbit anti-mouse Ig as measured on the FACS.

The pharmacologic regulation of interleukin-1 production: the role of prostaglandins.

The role of prostaglandins in the regulation of lipopolysaccharide (LPS)-induced interleukin-1 (IL-1) production by murine C3H/HeN resident peritoneal macrophages was studied. IL-1 production was initially studied in the presence of piroxicam and indomethacin, both inhibitors of prostaglandin biosynthesis. IL-1 was assayed using the IL-1-dependent proliferative response of C3H/HeJ thymocytes.

Murine type II collagen arthritis. Association of an acute-phase response with clinical course.

The acute-phase reactant, C-reactive protein, is a good index of disease activity in patients with rheumatoid arthritis. We examined the murine acute-phase reactant, serum amyloid P, as an index of disease in type II collagen-induced arthritis in 3 mouse strains. The onset of type II collagen-induced arthritis, which is characterized by paw swelling, is associated with a significant, but transient, elevation of serum amyloid P.

The mechanism of tumor allograft survival induced by CP-17,193.

CP-17,193 was examined in vivo for its immunosuppressive effects and for its promotion of E1(4) tumor allograft survival. At a dose of 10 mg/kg p.o.

Effects of levamisole on the proliferation of thymic lymphocyte subpopulations.

The ability of levamisole to enhance proliferation of murine lymphocyte preparations stimulated by concanavalin A was examined. Levamisole substantially augmented the proliferation of C57Bl/6 thymic lymphocytes, but had only marginal effects on the proliferation of splenic lymphocytes. The possibility that this difference was related to the degree of cell maturation was examined by peanut agglutinin fractionation of the thymic lymphocytes.

Anti-arthritic effect of bee venom.

Bee venom, administered subcutaneously, suppressed the development of carrageenan-induced paw edema and adjuvant arthritis in the rat in a dose-related manner. A single dose of bee venom administered subcutaneously the day before or on the day of injection of complete Freund's adjuvant (CFA) effectively suppressed the development of polyarthritis. This suppressive effect decreased progressively as dosing was delayed.