bimosiamose-disodium and Asthma

Airway inflammation is a hallmark of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Cell adhesion molecules play critical roles in the recruitment and migration of cells to sites of inflammation. Not surprisingly, these receptors have garnered the attention of the pharmaceutical industry as targets for the development of drugs to treat inflammatory and autoimmune diseases. Although several potential cell adhesion targets exist, development of compounds for pulmonary indications has centered around the selectins and the integrin VLA-4. In vitro and in vivo studies have implicated these receptors in the recruitment of inflammatory cells to the lung as well as to key cellular activation pathways. Several first generation compounds are currently in clinical development for asthma. Positive data from a phase II clinical trial using an inhaled formulation of a selectin antagonist has recently been reported. Initial results from clinical trials using first generation VLA-4 antagonists have been less promising but additional trials with more fully optimized compounds are underway. Results from these trials will provide insight into what the future holds for this exciting new class of drugs to treat pulmonary diseases.

Topics: Animals; Asthma; Biphenyl Compounds; Cell Adhesion Molecules; Chemistry, Pharmaceutical; Clinical Trials as Topic; Humans; Integrin alpha4beta1; Mannose; Mannosides; Phenylalanine; Pulmonary Disease, Chronic Obstructive; Selectins

Inhibition of selectin function is expected to aid in the management of diseases characterized by aberrant or chronic inflammation, as in asthma and chronic obstructive pulmonary disease (COPD). Selectin-mediated adhesion of leukocytes to the vascular endothelium is a critical early event in the initiation of the inflammatory response, making it a good target for therapeutic intervention. Many approaches to modulating selectin function have been explored, including competitive inhibition, altering cell-surface expression and inducing shedding/cleavage from the cell surface; however, clinical success has been elusive.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Biphenyl Compounds; Cell Adhesion; Chemotaxis, Leukocyte; Clinical Trials as Topic; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Ligands; Lung; Mannose; Mannosides; Membrane Glycoproteins; Oligosaccharides; Pulmonary Disease, Chronic Obstructive; Selectins; Sialyl Lewis X Antigen

Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%.. To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only.. Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge.. TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia.. We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.

Topics: Adult; Allergens; Analysis of Variance; Asthma; Biphenyl Compounds; Female; Forced Expiratory Volume; Humans; Infusions, Intravenous; Integrins; Lung; Male; Mannose; Mannosides; Skin Tests; Treatment Failure

Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma.

Topics: Anti-Asthmatic Agents; Asthma; Biphenyl Compounds; Cell Adhesion; HL-60 Cells; Humans; Mannose; Mannosides; Models, Molecular; Selectins