Search

Your search keyword '"Pozzani K"' showing total 2 results
Start Over Author "Pozzani K"
2 results on '"Pozzani K"'

1. Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.

Author

Hicks A, Goodnow R Jr, Cavallo G, Tannu SA, Ventre JD, Lavelle D, Lora JM, Satjawatcharaphong J, Brovarney M, Dabbagh K, Tare NS, Oh H, Lamb M, Sidduri A, Dominique R, Qiao Q, Lou JP, Gillespie P, Fotouhi N, Kowalczyk A, Kurylko G, Hamid R, Wright MB, Pamidimukkala A, Egan T, Gubler U, Hoffman AF, Wei X, Li YL, O'Neil J, Marcano R, Pozzani K, Molinaro T, Santiago J, Singer L, Hargaden M, Moore D, Catala AR, Chao LC, Benson J, March T, Venkat R, Mancebo H, and Renzetti LM

Subjects
Animals, Benzodioxoles therapeutic use, Benzodioxoles toxicity, Dogs, Drug-Related Side Effects and Adverse Reactions, Female, Guinea Pigs, HL-60 Cells, Humans, Hypersensitivity complications, Lipopolysaccharides pharmacology, Lung drug effects, Male, Mice, Ozone pharmacology, Phenylpropionates therapeutic use, Phenylpropionates toxicity, Pneumonia chemically induced, Pneumonia complications, Pneumonia metabolism, Rats, Receptors, Leukotriene B4 metabolism, Smoking adverse effects, Toxicity Tests, Benzodioxoles pharmacology, Phenylpropionates pharmacology, Pneumonia drug therapy, Primates, Receptors, Leukotriene B4 antagonists & inhibitors
Abstract

Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma., (Copyright 2010 Elsevier Inc. All rights reserved.)

Published
2010
Full Text
View/download PDF

2. Discovery of novel and potent leukotriene B4 receptor antagonists. Part 1.

Author

Goodnow RA Jr, Hicks A, Sidduri A, Kowalczyk A, Dominique R, Qiao Q, Lou JP, Gillespie P, Fotouhi N, Tilley J, Cohen N, Choudhry S, Cavallo G, Tannu SA, Ventre JD, Lavelle D, Tare NS, Oh H, Lamb M, Kurylko G, Hamid R, Wright MB, Pamidimukkala A, Egan T, Gubler U, Hoffman AF, Wei X, Li YL, O'Neil J, Marcano R, Pozzani K, Molinaro T, Santiago J, Singer L, Hargaden M, Moore D, Catala AR, Chao LC, Hermann G, Venkat R, Mancebo H, and Renzetti LM

Subjects
Animals, Drug Evaluation, Preclinical, Guinea Pigs, HL-60 Cells, Humans, Leukotriene Antagonists pharmacology, Phenyl Ethers chemistry, Primates, Protein Binding, Rats, Receptors, G-Protein-Coupled metabolism, Receptors, Leukotriene B4 metabolism, Structure-Activity Relationship, Drug Discovery, Leukotriene Antagonists chemistry, Phenyl Ethers pharmacology, Receptors, Leukotriene B4 antagonists & inhibitors
Abstract

The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

Published
2010
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results