Michael J. Sofia

Pharmacologic Actions of the Second-Generation Leukotriene B4 Receptor Antagonist LY293111: In Vitro Studies

Abstract. We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6α(2S*,3S*),8β(R*),9β,11α]-5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14xa0µg/kg) or p.o. (ED50=0.4xa0mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy-11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3xa0mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1xa0h, but not 2xa0h and 4xa0h post-exposure. We conclude that LY293111 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.

Effects of two leukotriene B4 (LTB4) receptor antagonists (LY255283 and SC-41930) on LTB4-induced human neutrophil adhesion and superoxide production.

Leukotriene B4 (LTB4) induces a number of functional changes in human neutrophils, including both superoxide release and CD11b/CD18 (Mo1)-mediated adherence to various substrates, such as keyhole limpet hemocyanin (KLH). These effects are both time- and concentration-dependent. Neutrophil adhesion was at least 10-fold more sensitive to the stimulatory action of LTB4 than superoxide production. Two LTB4 receptor antagonists, LY255283 (1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)heptyloxy )- phenyl)ethanone) and the sodium salt of SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8- propyl-2H- 1-benzopyran-2-carboxylic acid) were evaluated for effects on human neutrophil superoxide production and adhesion. Despite being more sensitive to LTB4-induced stimulation, neutrophil adhesion was at least 100-fold less sensitive to inhibition by LY255283 and SC-41930 than superoxide production. Both LTB4 receptor antagonists behaved similarly in these models. These compounds did not inhibit neutrophil responses induced by granulocyte/macrophage colony-stimulating factor (GM-CSF).

Flow cytometric evaluation of the effects of leukotriene B4 receptor antagonists (LY255283 and SC-41930) on calcium mobilization and integrin expression of activated human neutrophils

Leukotriene B4 (LTB4) is a naturally occurring eicosanoid mediator which chemoattracts and stimulates human neutrophils to an activated state. In an attempt to identify novel antiinflammatory drugs, synthetic LTB4 receptor antagonists have been developed in several laboratories. In this study, the effects of two such LTB4 receptor antagonists were examined for their influences on two elements of human neutrophil activation using flow cytometric techniques. Quantitative flow cytometric assays of human neutrophil intracellular calcium mobilization and up-regulation of integrin (CD11b/CD18) cell surface expression were developed and used to determine the potency and selectivity of compounds LY255283 and SC-41930 on these activities. Our results indicate that both compounds preferentially block these functions of LTB4-induced human neutrophil activation in a concentration dependent manner and fall in the 1-2 microM range of antagonist activity. Compound SC-41930 was approximately twice as potent as LY255283 in blocking the targeted agonist effects. Both compounds were approximately 100-fold less potent in blocking the same functions of interleukin-8-induced human neutrophil activation.

-alkoxyphenol leukotriene B4 receptor antagonists: effect of a chroman carboxylic acid.

Abstract Several ortho -alkoxyphenols containing a chroman carboxylic acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These antagonists were compared to their parent alkoxyphenols containing the tetrazole acid sidechain. These chroman containing antagonists retained their binding potency for human neutrophil receptors; however, showed enhanced potency against guinea pig receptors in both in vitro and in vivo systems.

alkoxyphenol leukotriene B4 receptor antagonists

Abstract A series of ortho -alkoxyphenols containing a tetrazole acid sidechain have been prepared as antagonists of leukotriene B4 receptors. These compounds were tested as receptor antagonists of human neutrophil and guinea pig lung membrane leukotriene B4 receptors. Compounds in this series were found to be up to 18-fold more potent than LY255283. These results indicate that the acyl group of the 1,2,4,5 substituted hydroxyacetophenone class of LTB4 antagonists is not critical to antagonist potency.

Chapter 12. Novel Approaches to Anti-Inflammatory Agents as Therapeutics for Pulmonary Disease

Publisher Summary This chapter discusses some major new approaches to anti-inflammatory therapy as they relate to pulmonary diseases. National Institutes of Health states that asthma should be treated foremost as an inflammatory disease. Evidence that supports a major role for an inflammatory component in pulmonary diseases, such as asthma, forms the positive clinical effects of steroid therapy. Development of novel entities that impact on the inflammation associated with pulmonary disease could constitute major therapeutic advancements. Novel approaches to anti-inflammatory therapy target the function of T-lymphocytes, mast cells, macrophages, neutrophils, and eosinophils by blocking cell adhesion, migration, and activation. Other new agents inhibit the production or effect of inflammatory mediators, the release of toxic oxygen metabolites and proteins, or inhibit degradative enzymes that some of these cells release. Before leukocytes can transit from the blood to pulmonary tissue, they must first adhere to the vascular endothelium. Close cell-to-cell interactions are critically important in this aspect of the inflammatory process. These intercellular communications are mediated by specific cell-surface glycoproteins, termed adhesion molecules, which are up-regulated in response to agents, such as cytokines and leukotrienes. Cytokines are intercellular regulatory proteins that differ from classical hormones. In that, they are usually made by more than one cell that have a wide range of biologic effects and generally act over short distances. It is possible that overproduction of specific cytokines contributes to the pathogenesis of pulmonary inflammatory diseases. However, it is not possible to predict that specific approaches can yield useful drugs.

2-alkyl-4-ethyl-5-[6-methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenol leukotriene B4 receptor antagonists

A series of 2-n-alkyl-4-ethyl-5-[6-methyl-6-(2H-tetrazol-5-yl)heptyloxy]phenols were prepared and shown to be potent leukotriene B4 (LTB4) receptor antagonists. They bound to the human neutrophil and guinea pig lung LTB4 receptors with high affinity. Each compound was also shown to be effective at antagonizing the effects of LTB4-induced integrin up-regulation on human neutrophils and on LTB4-mediated contraction of guinea pig lung parenchyma.

Chapter Fifteen - Nucleosides and Nucleotides for the Treatment of Viral Diseases

Abstract Nucleosides and nucleotides have played an important role in the treatment of viral diseases. The treatment of human immunodeficiency virus (HIV) infection has seen the introduction of no less than eight nucleos(t)ides into clinical practice where they have become the cornerstone of combination therapies. Nucleos(t)ides have become the standard of care for the treatment of hepatitis B virus (HBV) infection and are rapidly emerging as the backbone of future combination regimens for the treatment of hepatitis C virus (HCV) infection. The treatment of many other viral infections such as those caused by cytomegalovirus, herpes simplex virus, Epstein–Barr virus, and varicella zoster virus rely heavily on nucleos(t)ide-based therapies. Consequently, because of the broad utility and success of these molecules in the treatment of viral diseases, efforts continue to search for novel nucleos(t)ides that can have an impact in antiviral clinical practice. This review will focus on recent developments in the field of nucleos(t)ide antiviral drug discovery and development with emphasis on HIV, HBV, HCV, and Dengue virus.

Aerosolized LTB4 produces delayed onset increases in pulmonary gas trapping

Airway obstruction, as measured by increases in postmortem pulmonary gas trapping, and lung inflammatory changes were examined in guinea pigs exposed for up to 4 h to aerosols of leukotriene B4 (LTB4) or its non-chemotactic isomer, 6-trans-12-epi-LTB4. Airway obstruction and cytological responses in isomer-exposed animals were similar to those of unexposed control animals. LTB4-exposed animals had minimal inflammatory changes at 0.5 h but became dyspneic by 2 h and had increased airway obstruction, bronchoalveolar lavage neutrophils and eosinophils, and pulmonary tissue granulocyte scores. The LTB4-induced effects at 4 h were similar to those 2 h, except for further increase in BAL neutrophils and eosinophils. LTB4-induced airway obstructive and inflammatory changes were prevented by pretreatment with the LTB4 receptor antagonist SC-41930, but were unaffected by indomethacin. Thus, prolonged LTB4 inhalation can produce delayed onset airway obstruction that is stereospecific, cyclooxygenase-independent, and temporally associated with the influx of granulocytes into lung airways.

QSAR study of ortho-phenylphenol leukotriene B4 receptor antagonists

Abstract QSAR models for a series of o-phenylphenol LTB 4 receptor antagonist have been developed with regression analysis. These models related specific features, electronic, size and shape, of the substituent with biological activity. The models have predictive value and may be useful in assisting future synthetic direction within this series of compounds.