Search

Your search keyword '"A. Robert Catala"' showing total 2 results
Start Over Author "A. Robert Catala"
2 results on '"A. Robert Catala"'

1. Discovery of Novel and Potent Leukotriene B4 Receptor Antagonists. Part 1

Author

Tina Molinaro, Robert Alan Goodnow, Louis M. Renzetti, Alexandra Hicks, Satish Choudhry, Xin Wei, Gesine J. Hermann, Qi Qiao, Anjula Pamidimukkala, A. Robert Catala, Maureen Hargaden, Jian Ping Lou, Nadine Tare, John O’Neil, Ueli Gubler, Karen Pozzani, David J Moore, Jennifer Santiago, Ruben Marcano, Paul Gillespie, Rachid Hamid, Noal Cohen, Hyesun Oh, Lisa C. F. Chao, Laura Singer, Jefferson Wright Tilley, Romyr Dominique, Grazyna Kurylko, Ying L. Li, Radhika Venkat, Achyutharao Sidduri, Matthew Blake Wright, Ann F. Hoffman, Shahid Tannu, Gary Cavallo, Nader Fotouhi, Thomas Egan, Martin Lamb, Jessica D. Ventre, Agnieszka Kowalczyk, D Lavelle, and Helena Mancebo

Subjects
Primates, Leukotriene B4, medicine.drug_class, Guinea Pigs, Drug Evaluation, Preclinical, Receptors, Leukotriene B4, HL-60 Cells, Pharmacology, Receptors, G-Protein-Coupled, Guinea pig, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, medicine, Animals, Humans, Receptor, ADME, Chemistry, Phenyl Ethers, Leukotriene B4 receptor, Receptor antagonist, In vitro, Rats, Bioavailability, Biochemistry, Leukotriene Antagonists, Molecular Medicine, Protein Binding
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

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

Author

Anjula Pamidimukkala, Jian Ping Lou, Paul Gillespie, Rachid Hamid, Hyesun Oh, Thomas H. March, D Lavelle, Lisa C. F. Chao, Tina Molinaro, Matthew Blake Wright, Martin Brovarney, A. Robert Catala, John O’Neil, Agnieszka Kowalczyk, Louis M. Renzetti, Nader Fotouhi, Maureen Hargaden, John Satjawatcharaphong, Karen Pozzani, Xin Wei, Thomas Egan, Radhika Venkat, Ruben Marcano, Shahid Tannu, Karim Dabbagh, Helena Mancebo, Laura Singer, Martin Lamb, David J Moore, Jessica D. Ventre, Janet M. Benson, Ying L. Li, Jennifer Santiago, Ann F. Hoffman, Alexandra Hicks, Gary Cavallo, Jose M. Lora, Robert Alan Goodnow, Ueli Gubler, Romyr Dominique, Achyutharao Sidduri, Nadine Tare, Qi Qiao, and Grazyna Kurylko

Subjects
Budesonide, Lipopolysaccharides, Male, Primates, ARDS, Drug-Related Side Effects and Adverse Reactions, Physiology, Leukotriene B4, medicine.drug_class, Guinea Pigs, Receptors, Leukotriene B4, HL-60 Cells, Lung injury, Biochemistry, chemistry.chemical_compound, Mice, Dogs, Ozone, Toxicity Tests, medicine, Hypersensitivity, Animals, Humans, Benzodioxoles, Pulmonary Eosinophilia, Lung, Pharmacology, COPD, Phenylpropionates, business.industry, Smoking, hemic and immune systems, Cell Biology, Pneumonia, respiratory system, medicine.disease, Receptor antagonist, Neutrophilia, respiratory tract diseases, Rats, chemistry, Immunology, lipids (amino acids, peptides, and proteins), Female, medicine.symptom, business, circulatory and respiratory physiology, medicine.drug
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.

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results