In rheumatoid arthritis, dysregulation of both the adaptive (T and B cells) and the innate (dendritic cells, macrophages, neutrophils) immune responses result in a complex network of cytokines, chemokines and growth factors that initiate and perpetuate the pathogenesis of the disease. Vascular endothelial growth factor (VEGF) is a proangiogenic and proinflammatory cytokine which is elevated in the synovium of RA patients and which contributes to the pathology of the disease. Inhibitors of VEGF have been shown to suppress disease symptoms in animal models of RA. Recent advances in the understanding of the biologic activity of glycosaminoglycans (GAGs) led us to explore a hitherto unknown mechanism of drug action and to identify new small molecule therapeutics targeting chemokines and cytokines. Chemokines such as IL-8 or MCP-3 bind to GAGs to form chemokine gradients in the extracellular matrix. Cytokines such as VEGF also require binding to GAGs for full biological activity. Such cytokines and chemokines mediate inflammation in RA. We have identified a number of novel compounds that selectively inhibit pro-inflammatory chemokine and cytokine interactions with GAGs in vitro. One such compound, GTC-2380 was found to selectively inhibit VEGF-GAG binding at an IC50 = 0.14 ïM and to inhibit acute inflammatory responses in vivo in both carrageenan-induced paw edema and delayed-type hypersensitivity (DTH) animal models, and also to inhibit disease symptoms in an adjuvant arthritis animal model of RA. The aims of this Phase I study are to; (i) further optimize the GTC-2380 chemical series via medicinal chemistry for the purpose of improving the solubility and in vivo activity of the compounds resulting in at least two compounds of improved activity (Aim 1); and (ii) perform in vivo experiments with at least two lead compounds in two animal models of RA, adjuvant arthritis and collagen-induced arthritis (Aim 2). These efforts will lead to the generation of a preclinical development candidate for IND- enabling studies which, if Phase I is successful, will be the aim of a Phase II proposal. As with any drug which may interfere with innate immunity, increased susceptibility to infection is an issue and will be fully addressed in the safety pharmacology studies in Phase II. It is felt that the selectivity of these compounds will minimize the negative impact on normal immune function. This research program aims to develop a novel therapeutic with an improved benefit/risk profile for reducing pain, inflammation and swelling, and for preventing joint destruction and disability in RA patients when compared to known DMARDs.
Public Health Relevance Statement: Public Health Relevance: The goal of this program is to develop mechanistically novel therapeutics for autoimmune inflammatory disorders, with an initial focus on rheumatoid arthritis (RA). Despite recent recognition of the importance of early therapy with disease-modifying anti-rheumatic drugs (DMARDs), and the timely and judicious use of biologic response modifiers and immunosuppressants, it has not been possible to prevent devastating inflammation and joint destruction in all patients with RA. This research program aims to develop a novel therapeutic with an improved benefit/risk profile for reducing joint pain and swelling, inducing remission, and preventing joint destruction and disability when compared to known DMARDs.
Project Terms: Acute; Address; Adjuvant Arthritis; Affect; Animal Model; Animals; Ankle; Antirheumatic Agents; Arthralgia; Arthritis; arthritis therapy; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Benefits and Risks; Binding (Molecular Function); Biological; Biological Assay; Caliber; Carrageenan; Cartilage; cationic antimicrobial protein CAP 37; CCL7 gene; Chemicals; chemokine; Complex; cytokine; Cytokine Network Pathway; DBA/1 Mouse; Delayed Hypersensitivity; Dendritic Cells; Development; Digit structure; disability; Disease; Disease remission; Dose; Drug effect disorder; Drug Kinetics; Early treatment; Edema; Evaluation; Event; Extracellular Matrix; Generations; Glycosaminoglycans; Goals; Growth Factor; Heparin; Heparin Binding; Histologic; IL8 gene; immune function; Immune response; Immunosuppressive Agents; improved; In Vitro; in vitro testing; in vivo; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; inhibitor/antagonist; Inhibitory Concentration 50; joint destruction; Laboratories; Lead; Legal patent; Limb structure; macrophage; Maximum Tolerated Dose; Measures; Mediating; medical schools; Modeling; Modification; Mus; Natural Immunity; neutrophil; novel; novel therapeutics; Oral; Pain; Pathogenesis; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; phase 1 study; phase 2 study; polysulfated glycosaminoglycan; pre-clinical; preclinical evaluation; Predisposition; prevent; programs; public health relevance; Rattus; Research; research study; response; Rheumatoid Arthritis; Running; Safety; screening; Series; small molecule; Solubility; Swelling; Symptoms; Synovial Membrane; Synovitis; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; therapeutic target; thienopyridine; Toxic effect; Vascular Endothelial Growth Factors; Visual; water solubility; Wor
