bio-1211 and Asthma

To determine the inhibitory effects of BIO-1211, a very late antigen-4 (vla-4) antagonist, on bronchoconstriction and neutrophil adhesion in rats.. For evaluating ovalbumin-induced bronchoconstriction in the sensitized rats, the changes in lung resistance (RL) and lung dynamic compliance (C(dyn)) were determined after antigen challenge. Neutrophils from the rats were used to determine fibronectin and serum-induced cell adhesion. The effect of BIO-1211 on wheezing was determined after inhalation of histamine and acetylcholine in guinea pigs.. BIO-1211 aerosol at 1, 3 and 10 mg/ml significantly inhibited the changes in lung resistance and lung dynamic compliance after antigen challenge in the sensitized rats in a dose-dependent manner. BIO-1211 at 25, 50, 100 and 200 microgram/ml inhibited the fibronectin-induced neutrophil adhesion by 23.5%, 24.6%, 61.4% and 58.1%, respectively, and serum-induced adhesion by 29.9%, 35.9%, 35.3% and 15.4%, respectively. Inhalation of 10 mg/ml BIO-1211 did not show any protection against histamine and acetylcholine-induced bronchoconstriction.. BIO-1211 inhibits bronchoconstriction and neutrophil adhesion, which may be associated with its effect against bronchoconstriction in rats.

Topics: Administration, Inhalation; Animals; Asthma; Bronchoconstriction; Bronchodilator Agents; Cell Adhesion; Female; Guinea Pigs; Male; Neutrophils; Oligopeptides; Rats

An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.

Topics: Administration, Oral; Animals; Asthma; Integrin alpha4beta1; Mice; Morpholines; Piperidines

The leukocyte integrin very late antigen-4 (alpha(4)beta(1), CD49d/CD29) is an adhesion receptor that plays an important role in allergic inflammation and contributes to antigen-induced late responses (LAR) and airway hyperresponsiveness (AHR). In this study, we show that single doses of a new small-molecule, tight-binding inhibitor of alpha(4), BIO-1211, whether given by aerosol or intravenously, either before or 1.5 h after antigen challenge blocks allergen- induced LAR and post-antigen-induced AHR in allergic sheep. Multiple treatments with doses of BIO-1211 that were ineffective when given singly, were protective. BIO-1211 also provided dose-dependent inhibition of the early airway response (EAR) to antigen. In conjunction with the functional protection against the antigen-induced LAR and AHR, sheep treated with BIO-1211 before challenge showed significantly reduced: (1) numbers of eosinophils in bronchoalveolar lavage (BAL), (2) BAL levels of the inflammatory marker tissue kallikrein, and (3) numbers of inflammatory cells (lymphocytes, eosinophils, metachromatic staining cells, and neutrophils) in bronchial biopsies obtained after challenge when compared with corresponding biopsies after vehicle treatment. More importantly, we show for the first time that an inhibitor of alpha(4) was able to reverse post-antigen-induced AHR, thereby decreasing the time of recovery from the normal period of > 9 d to 3 d. Our results show that effective inhibition of antigen-induced airway responses can be achieved with single doses of a potent small-molecule inhibitor of alpha(4) and that such agents may be used therapeutically, as well as prophylactically, to alleviate allergen- induced inflammatory events. These data provide further support and extend the evidence for the role of alpha(4) integrins in the pathophysiologic events that follow airway antigen challenge.

Topics: Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Carbachol; Eosinophils; Integrin alpha4beta1; Integrin beta1; Integrins; Kallikreins; Oligopeptides; Receptors, Lymphocyte Homing; Receptors, Very Late Antigen; Sheep