pyrimidinones and Arthritis--Rheumatoid

Topics: Analgesics; Arthritis; Arthritis, Rheumatoid; Chemical Phenomena; Chemistry; Drug Therapy, Combination; Drug Tolerance; Gastrointestinal Hemorrhage; Humans; Indomethacin; Pain; Pyrimidinones

The clinical development of a candidate p38 kinase inhibitor was terminated because of its unexpectedly rapid clearance in human subjects. Its short half-life and metabolic profile in human beings were vastly different from that in rats, dogs, and monkeys characterized during routine pre-clinical studies. Mice generated the predominant drug (4-hydroxylated) metabolite produced in human beings, which was not found in other species. The data from a murine in vitro drug biotransformation assay that used liver extracts from 14 inbred mouse strains were analyzed by haplotype-based computational genetic analysis. This led to the identification of aldehyde oxidase-1 (AOX1) as the enzyme responsible for the rapid metabolism of this drug. Specific enzyme inhibitors and expressed recombinant enzymes were used to confirm that AOX catalyzed the formation of the 4-hydroxylated drug metabolite in mouse and man. Genetic variation within Aox1 regulated the level of hepatic Aox1 mRNA, AOX1 protein, and enzyme activity among the inbred strains. Thus, computational murine pharmacogenetic analysis can facilitate the identification and characterization of drug metabolism pathways that are differentially utilized by humans and other species.

Topics: Adolescent; Adult; Aldehyde Oxidase; Animals; Arthritis, Rheumatoid; Dogs; Female; Half-Life; Haplorhini; Humans; Liver; Male; Mice; Mice, Inbred Strains; p38 Mitogen-Activated Protein Kinases; Pharmacogenetics; Protein Kinase Inhibitors; Pyrimidinones; Rats; Rats, Inbred BB; Single-Blind Method; Species Specificity; Young Adult

The resolution of inflammation is an active response involving the interaction of pro-resolving mediators with specific receptors, such as N-formyl peptide receptor 2 (FPR2). FPRs represent potentially important therapeutic targets for the treatment of some pathologies, including asthma and rheumatoid arthritis. Previously, we identified selective or mixed FPR agonists with a pyridazin-3(2H)-one scaffold, all containing a 4-bromophenylacetamide fragment at N-2. The most effective compounds in this series were EC3, a potent mixed FPR1/FPR2/FPR3 agonist, and EC10, which had a preference for FPR1. We report here a new series of pyridinone and pyrimidindione derivatives containing the 4-(bromophenyl)acetamide substituent that was essential for activity in the pyridazinone series. All new compounds were evaluated for FPR agonist activity in HL60 cells transfected with FPR1 or FPR2 and in human neutrophils. While most of the pyridinone derivatives had reasonable FPR agonist activity in the submicromolar/micromolar range, the pyrimidindione derivatives were less active. Compound 2a (N-(4-bromophenyl)-2-[3-cyano-5-(3-methoxyphenyl)-6-methyl-2-oxopyridin-1(2H)-yl]acetamide) was the most active pyridinone derivative and had a 10-fold preference for FPR2 (EC

Topics: Animals; Arthritis, Rheumatoid; Cell Line, Tumor; Cells, Cultured; Drug Design; Humans; Male; Pyridones; Pyrimidinones; Rats, Sprague-Dawley; Receptors, Formyl Peptide

Several studies have suggested that chemokine receptors are important mediators of inflammatory response in rheumatoid arthritis (RA). B cells are also known to play an important role in RA pathology. C-X-C chemokine receptor type 3 (CXCR3) is considered a potential therapeutic target in different inflammatory diseases; however, the mechanism remains unclear. Here, we evaluated the potentially protective effect of AMG487, a selective CXCR3 antagonist, in collagen-induced arthritis (CIA) mouse model. CIA mice were treated with AMG487 (5 mg/kg) every 48 h, from day 21 until day 41. We then investigated the effect of AMG487 on NF-κB p65-, NOS2-, MCP-1-, TNF-α-, IFN-γ, IL-4-, and IL-27-producing CD19

Topics: Acetamides; Animals; Antigens, CD19; Arthritis, Experimental; Arthritis, Rheumatoid; Autoimmunity; B-Lymphocytes; Cells, Cultured; Cytokines; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred DBA; NF-kappa B; Pyrimidinones; Receptors, CXCR3; Signal Transduction

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by uncontrolled joint inflammation and damage to bone and cartilage. Previous studies have shown that chemokine receptors have important roles in RA development, and that blocking these receptors effectively inhibits RA progression. Our study was undertaken to investigate the role of AMG487, a selective CXCR3 antagonist, in DBA/1J mice bearing collagen-induced arthritis (CIA). Following induction of CIA, animals were treated with 5 mg/kg AMG487 intraperitoneally every 48 h, starting from day 21 until day 41 and evaluated for clinical score, and histological hallmarks of arthritic inflammation. We further investigated the effect of AMG487 on Th1 (T-bet), Th17 (IL-17A, RORγt, STAT3), Th22 (IL-22), and T regulatory (Treg; Foxp3 and IL-10) cells in splenic CXCR3

Topics: Acetamides; Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; Cytokines; Disease Progression; Male; Mice; Mice, Inbred DBA; Pyrimidinones; Receptors, CXCR3

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Bone Resorption; Disease Models, Animal; Inflammation; Osteoclasts; Pharmacokinetics; Protein Kinase Inhibitors; Protein Structure, Tertiary; Pyrimidinones; Rats; Receptor, Macrophage Colony-Stimulating Factor; Structure-Activity Relationship

Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.

Topics: Arthritis, Rheumatoid; Combinatorial Chemistry Techniques; Cytokines; Dose-Response Relationship, Drug; Drug Design; HSP27 Heat-Shock Proteins; Humans; Intracellular Signaling Peptides and Proteins; Leukocytes, Mononuclear; Lipopolysaccharides; Molecular Structure; Monocytes; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Pyrimidinones; Pyrroles; Tumor Necrosis Factor-alpha

The transient receptor potential (TRP) channels are important membrane sensors, responding to thermal, chemical, osmotic, or mechanical stimuli by activation of calcium and sodium fluxes. In this study, three distinct TRP channels were detected and their role established in mediating cytosolic free calcium concentration ([Ca(2+)](cyt)) response in tumor-derived SW982 synoviocytes and primary cultures of human synovial cells from patients with inflammatory arthropathies. As shown by fura-2 ratio measurements while cells were incubated in a temperature-regulated chamber, significant [Ca(2+)](cyt) elevation was elicited by rapid changes in bath temperature, application of TRPV1 receptor agonists capsaicin and resiniferatoxin, or a cold receptor stimulator, icilin. Temperature thresholds for calcium response were determined to be 12 +/- 1 degrees C for cold and 28 +/- 2 degrees C for heat activation. Temperature increases or decreases beyond these thresholds resulted in a significant rise in the magnitude of [Ca(2+)](cyt) spikes. Observed changes in [Ca(2+)](cyt) were completely abolished in calcium-free medium and thus resulted from direct calcium entry through TRP channels rather then by activation of voltage-dependent calcium channels. Two heat sensitive channels, TRPV1 and TRPV4, and a cold-sensitive channel, TRPA1, were detected by RT-PCR. Minimal mRNA for TRPV3 or TRPM8 was amplified. The RT-PCR results support the data obtained with the [Ca(2+)](cyt) measurements. We propose that the TRP channels are functionally expressed in human synoviocytes and may play a critical role in adaptive or pathological changes in articular surfaces during arthritic inflammation.

Topics: Arthritis, Rheumatoid; Calcium; Calcium Channels; Calcium Signaling; Capsaicin; Cell Line, Tumor; Cells, Cultured; Chondrocalcinosis; Cytosol; Diterpenes; Hot Temperature; Humans; Inflammation; Nerve Tissue Proteins; Pyrimidinones; RNA, Messenger; Synovial Membrane; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; TRPV Cation Channels

Ginger has a long history of medicinal use, particularly as an anti-inflammatory agent for a wide variety of diseases such as arthritis. Suppression of inflammation in arthritis is attributed to suppression of proinflammatory cytokines and chemokines produced by synoviocytes, chondrocytes, and leukocytes.. This study aimed to elucidate the effect of a combination ginger extract and its individual components on chemokine expression in human synoviocytes.. Human synoviocytes were incubated with 100 microg/mL combination ginger extract (GE) of Alpinia galanga (AG) and Zingiber officinale (ZO); AG extract alone; ZO extract alone; or control media, for 1 hour at 37 degrees C, 5% CO2. Cells were next activated with 1 ng/mL of tumor necrosis factor alpha (TNF-alpha) for 1 hour to determine macrophage chemotactic factor (MCP-1) and interferon-gamma activated protein (IP-10) mRNA levels using reverse transcriptase polymerase chain reaction (RT-PCR). Secreted MCP-1 and IP-10 were quantified by enzyme-linked immunosorbent assay (ELISA) following a 24 hour incubation period.. The GE combination was consistently more effective in decreasing chemokine mRNA and chemokine secreted protein levels than its individual components ZO or AG. In comparison, ZO was more effective than AG in suppressing chemokine expression.. The present study demonstrates that GE inhibits chemokine expression, and that the combination of ZO and AG components acts synergistically. This ginger formulation may be useful for suppressing inflammation due to arthritis.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cells, Cultured; Chemokine CXCL10; Chemokines; Enzyme-Linked Immunosorbent Assay; Humans; Neoplasm Proteins; Plant Extracts; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Thiazoles; Tumor Necrosis Factor-alpha; Zingiber officinale

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Carrageenan; Edema; Freund's Adjuvant; Pyridines; Pyrimidinones; Rats; Structure-Activity Relationship