|
Tested for percentage inhibition of PTH stimulated bone resorption in neonatal mouse calvaria placed in culture, at 10 uM concentration
|
Mus musculus
|
95.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1-Naphthylmethylphosphonic acid derivatives as osteoclastic acid phosphatase inhibitors
Year : 1995
Volume : 5
Issue : 16
First Page : 1801
Last Page : 1806
Authors : Schwender CF, Beers SA, Malloy E, Demarest K, Minor L, Lau K
|
Decreased dry tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 100 mg/kg
|
Mus musculus
|
63.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased dry tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 100 mg/kg after 9 days
|
Mus musculus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased dry tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 200 mg/kg
|
Mus musculus
|
59.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased dry tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 25 mg/kg
|
Mus musculus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased dry tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 50 mg/kg
|
Mus musculus
|
47.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased wet tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 100 mg/kg
|
Mus musculus
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased wet tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 100 mg/kg after 9 days
|
Mus musculus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased wet tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 200 mg/kg
|
Mus musculus
|
55.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased wet tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 25 mg/kg
|
Mus musculus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Decreased wet tissue weight of DTH-GRA from mice was determined after (sc) administration of a dose of 50 mg/kg
|
Mus musculus
|
48.0
%
|
|
Journal : J. Med. Chem.
Title : Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1994
Volume : 37
Issue : 26
First Page : 4449
Last Page : 4454
Authors : Nugent RA, Schlachter ST, Murphy M, Dunn CJ, Staite ND, Galinet LA, Shields SK, Wu H, Aspar DG, Richard KA.
Abstract : A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 10 mg/kg in the non-injected paw
|
Mus musculus
|
61.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 100 mg/kg
|
Mus musculus
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 15 mg/kg
|
Mus musculus
|
46.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 200 mg/kg
|
Mus musculus
|
52.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 30 mg/kg
|
Mus musculus
|
46.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 5 mg/kg
|
Mus musculus
|
4.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 5 mg/kg in the non-injected paw
|
Mus musculus
|
51.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of antigen-induced polyarthritis (AIP) in mice at the dose of 50 mg/kg
|
Mus musculus
|
46.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of delayed type hypersensitivity granuloma results at 100 mg/kg in dry weight
|
Mus musculus
|
47.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of delayed type hypersensitivity granuloma results at 100 mg/kg in wet weight
|
Mus musculus
|
45.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Compound was tested for anti-inflammatory activity in delayed type hypersensitivity granuloma upon 100 mg/kg peroral administration
|
Mus musculus
|
48.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters.
Year : 1998
Volume : 8
Issue : 9
First Page : 1093
Last Page : 1096
Authors : Schlachter ST, Galinet LA, Shields SK, Aspar DG, Dunn CJ, Staite ND, Nugent RA.
Abstract : Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.
|
Compound was tested for antiarthritic activity in murine model of antigen-induced arthritis upon 100 mg/kg peroral administration
|
Mus musculus
|
42.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters.
Year : 1998
Volume : 8
Issue : 9
First Page : 1093
Last Page : 1096
Authors : Schlachter ST, Galinet LA, Shields SK, Aspar DG, Dunn CJ, Staite ND, Nugent RA.
Abstract : Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 10 mg/kg in the injected paw
|
Rattus norvegicus
|
38.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 15 mg/kg in the injected paw
|
Rattus norvegicus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 15 mg/kg in the non-injected paw
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 30 mg/kg in the injected paw
|
Rattus norvegicus
|
36.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 30 mg/kg in the non-injected paw
|
Rattus norvegicus
|
54.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of rat adjuvant induced polyarthritis (AIP) at the dose of 5 mg/kg in the injected paw
|
Rattus norvegicus
|
21.0
%
|
|
Journal : J. Med. Chem.
Title : Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.
Year : 1993
Volume : 36
Issue : 1
First Page : 134
Last Page : 139
Authors : Nugent RA, Murphy M, Schlachter ST, Dunn CJ, Smith RJ, Staite ND, Galinet LA, Shields SK, Aspar DG, Richard KA.
Abstract : Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.
|
Inhibition of Escherichia coli F plasmid TraI relaxase Y16F mutant assessed as oriT ssDNA cleavage by competitive inhibition assay
|
Escherichia coli
|
3.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase.
Year : 2007
Volume : 104
Issue : 30
First Page : 12282
Last Page : 12287
Authors : Lujan SA, Guogas LM, Ragonese H, Matson SW, Redinbo MR.
Abstract : Conjugative transfer of plasmid DNA via close cell-cell junctions is the main route by which antibiotic resistance genes spread between bacterial strains. Relaxases are essential for conjugative transfer and act by cleaving DNA strands and forming covalent phosphotyrosine linkages. Based on data indicating that multityrosine relaxase enzymes can accommodate two phosphotyrosine intermediates within their divalent metal-containing active sites, we hypothesized that bisphosphonates would inhibit relaxase activity and conjugative DNA transfer. We identified bisphosphonates that are nanomolar inhibitors of the F plasmid conjugative relaxase in vitro. Furthermore, we used cell-based assays to demonstrate that these compounds are highly effective at preventing DNA transfer and at selectively killing cells harboring conjugative plasmids. Two potent inhibitors, clodronate and etidronate, are already clinically approved to treat bone loss. Thus, the inhibition of conjugative relaxases is a potentially novel antimicrobial approach, one that selectively targets bacteria capable of transferring antibiotic resistance and generating multidrug resistant strains.
|
Inhibition of conjugate DNA transfer between tetracycline-resistant F plasmid positive Escherichia coli JS10 to streptomycin-resistant F plasmid deficient Escherichia coli JS4
|
Escherichia coli
|
110.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase.
Year : 2007
Volume : 104
Issue : 30
First Page : 12282
Last Page : 12287
Authors : Lujan SA, Guogas LM, Ragonese H, Matson SW, Redinbo MR.
Abstract : Conjugative transfer of plasmid DNA via close cell-cell junctions is the main route by which antibiotic resistance genes spread between bacterial strains. Relaxases are essential for conjugative transfer and act by cleaving DNA strands and forming covalent phosphotyrosine linkages. Based on data indicating that multityrosine relaxase enzymes can accommodate two phosphotyrosine intermediates within their divalent metal-containing active sites, we hypothesized that bisphosphonates would inhibit relaxase activity and conjugative DNA transfer. We identified bisphosphonates that are nanomolar inhibitors of the F plasmid conjugative relaxase in vitro. Furthermore, we used cell-based assays to demonstrate that these compounds are highly effective at preventing DNA transfer and at selectively killing cells harboring conjugative plasmids. Two potent inhibitors, clodronate and etidronate, are already clinically approved to treat bone loss. Thus, the inhibition of conjugative relaxases is a potentially novel antimicrobial approach, one that selectively targets bacteria capable of transferring antibiotic resistance and generating multidrug resistant strains.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
5.6
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in injected paw at 50 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
35.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in injected paw at 30 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
34.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in injected paw at 20 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
28.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in injected paw at 10 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
23.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in non-injected paw at 50 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
68.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in non-injected paw at 30 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
62.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in non-injected paw at 20 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
70.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiarthritic activity in complete Freund's adjuvant-induced rat arthritis model assessed as reduction of paw volume in non-injected paw at 10 mg/kg, sc qd for 28 days
|
Rattus norvegicus
|
56.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma dry weight at 100 mg/kg, sc qd for 9 days
|
Mus musculus
|
48.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma dry weight at 60 mg/kg, sc qd for 9 days
|
Mus musculus
|
44.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma dry weight at 25 mg/kg, sc qd for 9 days
|
Mus musculus
|
33.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma wet weight at 100 mg/kg, sc qd for 9 days
|
Mus musculus
|
44.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma wet weight at 60 mg/kg, sc qd for 9 days
|
Mus musculus
|
40.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
|
Antiinflammatory activity in methylated bovine serum albumin sensitized delayed-type hypersensitivity granuloma mouse model assessed as reduction of granuloma wet weight at 25 mg/kg, sc qd for 9 days
|
Mus musculus
|
30.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inhibitory effect of novel S,N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation.
Year : 2012
Volume : 51
First Page : 239
Last Page : 249
Authors : Kamel AA, Geronikaki A, Abdou WM.
Abstract : A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.
