Jeannie M. Arruda
General Atomics
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Publication
Featured researches published by Jeannie M. Arruda.
Journal of Medicinal Chemistry | 2009
John H. Hutchinson; Yiwei Li; Jeannie M. Arruda; Christopher Baccei; Gretchen Bain; Charles Chapman; Lucia Correa; Janice Darlington; Christopher King; Catherine Lee; Dan Lorrain; Pat Prodanovich; Haojing Rong; Angelina M. Santini; Nicholas Simon Stock; Peppi Prasit; Jilly F. Evans
The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.
Journal of Pharmacology and Experimental Therapeutics | 2009
Daniel S. Lorrain; Gretchen Bain; Lucia Correa; Charles Chapman; Alex R. Broadhead; Angelina M. Santini; Pat Prodanovich; Janice Darlington; John H. Hutchinson; Christopher King; Catherine Lee; Christopher Baccei; Yiwei Li; Jeannie M. Arruda; Jilly F. Evans
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA4 by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB4 assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC50 of ∼60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB4 and cysteinyl leukotriene (CysLT) production with ED50 values of 0.8 and 1 mg/kg, respectively. In this model, the EC50 derived from plasma AM103 was ∼330 nM for inhibition of both LTB4 and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB4, CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
Archive | 2002
Jeannie M. Arruda; Celine Bonnefous; Brian T. Campbell; Rowena V. Cube; Benito Munoz; Brian Andrew Stearns; Jean-Michel Vernier; Bowei Wang; Xiumin Zhao
Archive | 2009
John Howard Hutchinson; Thomas Jon Seiders; Bowei Wang; Jeannie M. Arruda; Jeffrey Roger Roppe; Timothy Parr
Archive | 2009
John Howard Hutchinson; Thomas Jon Seiders; Bowei Wang; Jeannie M. Arruda; Brian Andrew Stearns
Archive | 2009
John Howard Hutchinson; Brian Andrew Stearns; Jill Melissa Scott; Yen Pham Truong; Jeffrey Roger Roppe; Nicholas Simon Stock; Jeannie M. Arruda; Thomas Jon Seiders; Bowei Wang; Deborah Volkots
Archive | 2009
John Howard Hutchinson; Thomas Jonathan Seiders; Brian Andrew Stearns; Bowei Wang; Yen Pham Truong; Jeannie M. Arruda
Archive | 2010
John Howard Hutchinson; Thomas Jon Seiders; Bowei Wang; Jeannie M. Arruda; Jeffrey Roger Roppe; Timothy Parr
Archive | 2009
John Howard Hutchinson; Thomas Jon Seiders; Jeannie M. Arruda; Jeffrey Roger Roppe
Bioorganic & Medicinal Chemistry Letters | 2004
Tao Hu; Brian Andrew Stearns; Brian T. Campbell; Jeannie M. Arruda; Chixu Chen; Jayashree Aiyar; Robert E Bezverkov; Angelina Santini; Hervé Schaffhauser; Wensheng Liu; Shankar Venkatraman; Benito Munoz