What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseasesJilly F Evans
Amira Pharmaceuticals, 9535 Waples Street, San Diego, CA 92121, USA
Trends Pharmacol Sci 29:72-8. 2008
..In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design...
- Pharmacology of AM803, a novel selective five-lipoxygenase-activating protein (FLAP) inhibitor in rodent models of acute inflammation
Daniel S Lorrain
Amira Pharmaceuticals, 9535 Waples Street, Ste 100, San Diego, California 92121, USA
Eur J Pharmacol 640:211-8. 2010
..In summary, AM803 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute inflammation and in a model of lethal shock...
- Pharmacology of AM211, a potent and selective prostaglandin D2 receptor type 2 antagonist that is active in animal models of allergic inflammation
Gretchen Bain
Amira Pharmaceuticals, San Diego, California 92121, USA
J Pharmacol Exp Ther 338:290-301. 2011
..AM211 represents a potent and selective antagonist of DP2 that may be used clinically to evaluate the role of DP2 in T helper 2-driven allergic inflammatory diseases...
- 5-Lipoxygenase-activating protein inhibitors. Part 3: 3-{3-tert-Butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM643)-A potent FLAP inhibitor suitable for topical administ
Nicholas Stock
Amira Pharmaceuticals, San Diego, CA 92121, USA
Bioorg Med Chem Lett 20:4598-601. 2010
..Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling...
- Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis
Jill M Scott
Amira Pharmaceuticals, 9535 Waples Street, Suite 100, San Diego, CA 92121, USA
Bioorg Med Chem Lett 21:6608-12. 2011
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- 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 inhib
Nicholas S Stock
Department of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, United States
J Med Chem 54:8013-29. 2011
..This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients...
- 5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)--a potent FLAP inhibitor
Nicholas Stock
Amira Pharmaceuticals, 9535 Waples St, Suite 100, San Diego, CA 92121, USA
Bioorg Med Chem Lett 20:213-7. 2010
..Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model...
- Pharmacological characterization of 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), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute
Daniel S Lorrain
Amira Pharmaceuticals, San Diego, California 92121, USA
J Pharmacol Exp Ther 331:1042-50. 2009
..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...
- DP2 (CRTh2) antagonism reduces ocular inflammation induced by allergen challenge and respiratory syncytial virus
Karin J Stebbins
Amira Pharmaceuticals, San Diego, Calif, USA
Int Arch Allergy Immunol 157:259-68. 2012
..PGD(2), therefore, may be involved in both early and late phase reactions in response to allergen challenge...
- Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation
Karin J Stebbins
Amira Pharmaceuticals, 9535 Waples St, Ste 100 San Diego, CA 92121, USA
Eur J Pharmacol 638:142-9. 2010
..These results suggest that selective prostanoid DP(2) receptor antagonists such as AM156 may provide beneficial effects for the clinical treatment of diseases such as allergic rhinitis and asthma...
- Sodium [2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4'-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetate (AM432): a potent, selective prostaglandin D2 receptor antagonist
Nicholas Stock
Amira Pharmaceuticals, 9535 Waples St, San Diego, CA 92121, USA
Bioorg Med Chem Lett 21:1036-40. 2011
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- 5-lipoxygenase-activating protein inhibitors: development of 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)
John H Hutchinson
Departments of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, USA
J Med Chem 52:5803-15. 2009
..Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers...
Expression, purification and crystallization of human 5-lipoxygenase-activating protein with leukotriene-biosynthesis inhibitorsShihua Xu
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Acta Crystallogr Sect F Struct Biol Cryst Commun 63:1054-7. 2007
..The crystals exhibit tetragonal symmetry (P42(1)2) and diffracted to a resolution limit of 4 A...
The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysmLei Zhao
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA
Nat Med 10:966-73. 2004
..These data link the 5-LO pathway to hyperlipidemia-dependent inflammation of the arterial wall and to pathogenesis of aortic aneurysms through a potential chemokine intermediary route...
- The cysteinyl leukotriene receptors
Jilly F Evans
Pharmacology Department, Merck Research Laboratories, Merck and Co, Inc, 770 Sumneytown Pike, West Point, PA 19486, USA
Prostaglandins Leukot Essent Fatty Acids 69:117-22. 2003
..Two human and mouse CysLT receptors have been molecularly cloned and characterized. The properties of these receptors agrees well with previous pharmacological CysLT agonist and antagonist characterizations of the CysLT receptors...
- A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha
Miles D Thompson
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Pharmacogenetics 13:641-9. 2003
..0015). This represents the first association of a coding mutation in the CysLT2 receptor gene, located on chromosome 13q14, with the atopic phenotype found in the Tristan da Cunha population...
- Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4
Guochang Yang
Center for Experimental Therapeutics, Rm 814BRBII III, Univ of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104 6160, USA
Am J Physiol Lung Cell Mol Physiol 286:L992-1001. 2004
..These results indicate that a selective hCysLT(1)R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT(1)R signaling contributes to a hypercontractile state of the airway smooth muscle...
- The membrane organization of leukotriene synthesis
Asim K Mandal
Department of Medicine, Massachusetts General Hospital, 149 The Navy Yard, 13th Street, Charlestown, MA 02129, USA
Proc Natl Acad Sci U S A 101:6587-92. 2004
..The results indicate that the formation of LTC(4) and LTB(4) may be determined by the compartmentalization of biosynthetic enzymes in discrete molecular complexes...
- Localization and upregulation of cysteinyl leukotriene-1 receptor in asthmatic bronchial mucosa
Jie Zhu
Lung Pathology, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom
Am J Respir Cell Mol Biol 33:531-40. 2005
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- Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells
Barbara Uzonyi
Institute for Vascular Medicine aud Institute for Medical Statistics, Computer Sciences, and Documentation, Friedrich Schiller University, Bachstrasse 18, 07743 Jena, Germany
Proc Natl Acad Sci U S A 103:6326-31. 2006
..These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury...
- Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein
Andrew D Ferguson
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
Science 317:510-2. 2007
..This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases...
- Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice
Min Yao
Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118, USA
Cancer Res 63:586-92. 2003
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