5-Lipoxygenase-Activating Protein (FLAP) Inhibitors. Part 4: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic Acid (AM803), a Potent, Oral, Once Daily FLAP Inhibitor
| Autor: | Charles Chapman, Alex R. Broadhead, Peppi Prasit, Christopher Baccei, Nicholas Simon Stock, Yiwei Li, Jeffrey Roger Roppe, Angelina M. Santini, Dan Lorrain, Lucia Correa, Gretchen Bain, Jasmine Eleanor Zunic, Jeannie Ziff, Christopher D. King, Catherine Lee, Pat Prodanovich, Janice Darlington, Haojing Rong, Jilly F. Evans, Hutchinson John H |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Indoles Stereochemistry Administration Oral In Vitro Techniques Bronchoalveolar Lavage Rats Sprague-Dawley Structure-Activity Relationship Dogs Pharmacokinetics Drug Discovery medicine Animals Cytochrome P-450 Enzyme Inhibitors Humans Potency Anti-Asthmatic Agents 5-lipoxygenase-activating protein Pentanoic Acids Whole blood medicine.diagnostic_test biology Chemistry Pyridine moiety Rats Bronchoalveolar lavage 5-Lipoxygenase-Activating Protein Inhibitors Pharmacodynamics biology.protein Molecular Medicine Female Once daily |
| Zdroj: | Journal of Medicinal Chemistry. 54:8013-8029 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm2008369 |
| Popis: | The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients. |
| Databáze: | OpenAIRE |
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