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Antiarthritic Activity

The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform

Irmgard Wiesenberg – 1st expert on this subject based on the ideXlab platform

  • Specific Activation of the Nuclear Receptors PPARγ and RORA by the Antidiabetic Thiazolidinedione BRL 49653 and the Antiarthritic Thiazolidinedione Derivative CGP 52608
    Molecular Pharmacology, 1998
    Co-Authors: Irmgard Wiesenberg, Martin Missbach, Michele Chiesi, Carsten Spanka, Werner Pignat, Carsten Carlberg

    Abstract:

    The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor γ (PPARγ) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor α (RORA) and exhibits potent Antiarthritic Activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARγ, RORA, and retinoic acid receptor α, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARγ-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent Antiarthritic Activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARγ and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.

  • thiazolidine diones specific ligands of the nuclear receptor retinoid z receptor retinoid acid receptor related orphan receptor α with potent Antiarthritic Activity
    Journal of Biological Chemistry, 1996
    Co-Authors: Martin Missbach, Bruno Jagher, Ivo Sigg, Sepideh Nayeri, Carsten Carlberg, Irmgard Wiesenberg

    Abstract:

    Abstract Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease with many similarities to rheumatoid arthritis. We have identified a class of thiazolidine diones with high potency in suppressing chronic inflammation and joint destruction in this experimental model. The lead compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits Antiarthritic Activity at daily oral doses between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor α (RZR/RORα) in low nanomolar concentrations. This receptor is a novel member of the superfamily of ligand-inducible transcription factors, and we have recently identified the pineal gland hormone melatonin as a natural ligand. Structure-Activity relationship studies with 13 closely related analogues of CGP 52608 revealed a striking correlation between RZR/RORα activation and Antiarthritic Activity. We therefore suggest that nuclear signaling via RZR/RORα is a key mechanism in mediating the Antiarthritic effects of these thiazolidine diones and may open a novel therapeutic approach for the treatment of rheumatoid arthritis and other autoimmune diseases. The existence of a nuclear melatonin receptor may lead to a better understanding of the immunomodulatory actions of melatonin.

  • Thiazolidine Diones, Specific Ligands of the Nuclear Receptor Retinoid Z Receptor/Retinoid Acid Receptor-related Orphan Receptor α with Potent Antiarthritic Activity
    Journal of Biological Chemistry, 1996
    Co-Authors: Martin Missbach, Bruno Jagher, Ivo Sigg, Sepideh Nayeri, Carsten Carlberg, Irmgard Wiesenberg

    Abstract:

    Abstract Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease with many similarities to rheumatoid arthritis. We have identified a class of thiazolidine diones with high potency in suppressing chronic inflammation and joint destruction in this experimental model. The lead compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits Antiarthritic Activity at daily oral doses between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor α (RZR/RORα) in low nanomolar concentrations. This receptor is a novel member of the superfamily of ligand-inducible transcription factors, and we have recently identified the pineal gland hormone melatonin as a natural ligand. Structure-Activity relationship studies with 13 closely related analogues of CGP 52608 revealed a striking correlation between RZR/RORα activation and Antiarthritic Activity. We therefore suggest that nuclear signaling via RZR/RORα is a key mechanism in mediating the Antiarthritic effects of these thiazolidine diones and may open a novel therapeutic approach for the treatment of rheumatoid arthritis and other autoimmune diseases. The existence of a nuclear melatonin receptor may lead to a better understanding of the immunomodulatory actions of melatonin.

Martin Missbach – 2nd expert on this subject based on the ideXlab platform

  • Specific Activation of the Nuclear Receptors PPARγ and RORA by the Antidiabetic Thiazolidinedione BRL 49653 and the Antiarthritic Thiazolidinedione Derivative CGP 52608
    Molecular Pharmacology, 1998
    Co-Authors: Irmgard Wiesenberg, Martin Missbach, Michele Chiesi, Carsten Spanka, Werner Pignat, Carsten Carlberg

    Abstract:

    The thiazolidinedione BRL 49653 and the thiazolidinedione derivative CGP 52608 are lead compounds of two pharmacologically different classes of compounds. BRL 49653 is a high affinity ligand of peroxisome proliferator-activated receptor γ (PPARγ) and a prototype of novel antidiabetic agents, whereas CGP 52608 activates retinoic acid receptor-related orphan receptor α (RORA) and exhibits potent Antiarthritic Activity. Both receptors belong to the superfamily of nuclear receptors and are structurally related transcription factors. We tested BRL 49653 and CGP 52608 for receptor specificity on PPARγ, RORA, and retinoic acid receptor α, a closely related receptor to RORA, and compared their pharmacological properties in in vitro and in vivo models in which these compounds have shown typical effects. BRL 49653 specifically induced PPARγ-mediated gene activation, whereas CGP 52608 specifically activated RORA in transiently transfected cells. Both compounds were active in nanomolar concentrations. Leptin production in differentiated adipocytes was inhibited by nanomolar concentrations of BRL 49653 but not by CGP 52608. BRL 49653 antagonized weight loss, elevated blood glucose levels, and elevated plasma triglyceride levels in an in vivo model of glucocorticoid-induced insulin resistance in rats, whereas CGP 52608 exhibited steroid-like effects on triglyceride levels and body weight in this model. In contrast, potent Antiarthritic Activity in rat adjuvant arthritis was shown for CGP 52608, whereas BRL 49653 was nearly inactive. Our results support the concept that transcriptional control mechanisms via the nuclear receptors PPARγ and RORA are responsible at least in part for the different pharmacological properties of BRL 49653 and CGP 52608. Both compounds are prototypes of interesting novel therapeutic agents for the treatment of non-insulin-dependent diabetes mellitus and rheumatoid arthritis.

  • thiazolidine diones specific ligands of the nuclear receptor retinoid z receptor retinoid acid receptor related orphan receptor α with potent Antiarthritic Activity
    Journal of Biological Chemistry, 1996
    Co-Authors: Martin Missbach, Bruno Jagher, Ivo Sigg, Sepideh Nayeri, Carsten Carlberg, Irmgard Wiesenberg

    Abstract:

    Abstract Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease with many similarities to rheumatoid arthritis. We have identified a class of thiazolidine diones with high potency in suppressing chronic inflammation and joint destruction in this experimental model. The lead compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits Antiarthritic Activity at daily oral doses between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor α (RZR/RORα) in low nanomolar concentrations. This receptor is a novel member of the superfamily of ligand-inducible transcription factors, and we have recently identified the pineal gland hormone melatonin as a natural ligand. Structure-Activity relationship studies with 13 closely related analogues of CGP 52608 revealed a striking correlation between RZR/RORα activation and Antiarthritic Activity. We therefore suggest that nuclear signaling via RZR/RORα is a key mechanism in mediating the Antiarthritic effects of these thiazolidine diones and may open a novel therapeutic approach for the treatment of rheumatoid arthritis and other autoimmune diseases. The existence of a nuclear melatonin receptor may lead to a better understanding of the immunomodulatory actions of melatonin.

  • Thiazolidine Diones, Specific Ligands of the Nuclear Receptor Retinoid Z Receptor/Retinoid Acid Receptor-related Orphan Receptor α with Potent Antiarthritic Activity
    Journal of Biological Chemistry, 1996
    Co-Authors: Martin Missbach, Bruno Jagher, Ivo Sigg, Sepideh Nayeri, Carsten Carlberg, Irmgard Wiesenberg

    Abstract:

    Abstract Rat adjuvant arthritis is a chronic T cell-dependent autoimmune disease with many similarities to rheumatoid arthritis. We have identified a class of thiazolidine diones with high potency in suppressing chronic inflammation and joint destruction in this experimental model. The lead compound CGP 52608 (1-(3-allyl-4-oxothiazolidine-2-ylidene)-4-methylthiosemicarbazone) exhibits Antiarthritic Activity at daily oral doses between 0.01 and 1 mg/kg and was shown to specifically activate the retinoid Z receptor/retinoid acid receptor-related orphan receptor α (RZR/RORα) in low nanomolar concentrations. This receptor is a novel member of the superfamily of ligand-inducible transcription factors, and we have recently identified the pineal gland hormone melatonin as a natural ligand. Structure-Activity relationship studies with 13 closely related analogues of CGP 52608 revealed a striking correlation between RZR/RORα activation and Antiarthritic Activity. We therefore suggest that nuclear signaling via RZR/RORα is a key mechanism in mediating the Antiarthritic effects of these thiazolidine diones and may open a novel therapeutic approach for the treatment of rheumatoid arthritis and other autoimmune diseases. The existence of a nuclear melatonin receptor may lead to a better understanding of the immunomodulatory actions of melatonin.

Shashi Bhushan – 3rd expert on this subject based on the ideXlab platform

  • pyrano isochromanones as il 6 inhibitors synthesis in vitro and in vivo Antiarthritic Activity
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Shreyans K. Jain, Surjeet Singh, Anamika Khajuria, Santosh Kumar Guru, Prashant Joshi, Samdarshi Meena, Janhavi R. Nadkarni, Amarinder Singh, Sonali S. Bharate, Shashi Bhushan

    Abstract:

    Bergenin (1), a unique fused C-glycoside isolated from Bergenia species, possesses interesting anti-inflammatory and antipain activities. To study SAR of this scaffold, first-generation derivatives were synthesized and evaluated for inhibition of lymphocyte proliferation and production of pro-inflammatory cytokines. The C-7 substituted derivatives showed inhibition of IL-6 as well as TNF-α production. Bergenin and its most potent IL-6 inhibitor derivatives 4e and 4f were then investigated in a panel of in vitro and in vivo inflammation/arthritis models. These compounds significantly decreased the expression of NF-kB and IKK-β in THP-1 cells. In in vivo study in BALB/c mice, a dose-dependent inhibition of SRBC-induced cytokines, reduction in humoral/cell-mediated immunity, and antibody titer was observed. The CIA study in DBA/1J mice indicated that compounds led to reduction in swelling of paws, cytokine levels, and anticollagen IgG1/IgG2a levels. The significant in vivo immunosuppressive efficacy of pyran…

  • Pyrano-isochromanones as IL-6 inhibitors: Synthesis, in vitro and in vivo Antiarthritic Activity
    Journal of Medicinal Chemistry, 2014
    Co-Authors: Shreyans K. Jain, Surjeet Singh, Anamika Khajuria, Santosh Kumar Guru, Prashant Joshi, Samdarshi Meena, Janhavi R. Nadkarni, Amarinder Singh, Sonali S. Bharate, Shashi Bhushan

    Abstract:

    Bergenin (1), a unique fused C-glycoside isolated from Bergenia species, possesses interesting anti-inflammatory and antipain activities. To study SAR of this scaffold, first-generation derivatives were synthesized and evaluated for inhibition of lymphocyte proliferation and production of proinflammatory cytokines. The C-7 substituted derivatives showed inhibition of IL-6 as well as TNF-alpha production. Bergenin and its most potent IL-6 inhibitor derivatives 4e and 4f were then investigated in a panel of in vitro and in vivo inflammation/arthritis models. These compounds significantly decreased the expression of NF-kB and IKK-beta in THP-1 cells. In in vivo study in BALB/c mice, a dose-dependent inhibition of SRBC-induced cytokines, reduction in humoral/cell-mediated immunity, and antibody titer was observed. The CIA study in DBA/1J mice indicated that compounds led to reduction in swelling of paws, cytokine levels, and anticollagen IgG1/IgG2a levels. The significant in vivo immunosuppressive efficacy of pyrano-isochromanones demonstrates the promise of this scaffold for development of next-generation Antiarthritic drugs.