Pharmacodynamics and Pharmacokinetics of AM103, a Novel Inhibitor of 5-Lipoxygenase-Activating Protein ( )

The 5‐lipoxygenase‐activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3‐[3‐tert‐butylsulfanyl‐1‐[4‐(6‐methoxy‐pyridin‐3‐yl)‐benzyl]...

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Published in:	Clinical pharmacology and therapeutics Vol. 87; no. 4; pp. 437 - 444
Main Authors:	Bain, G, King, C D, Rewolinski, M, Schaab, K, Santini, A M, Shapiro, D, Moran, M, Wetering de Rooij, S, Roffel, A F, Schuilenga‐Hut, P, Milne, G L, Lorrain, D S, Li, Y, Arruda, J M, Hutchinson, J H, Prasit, P, Evans, J F
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-04-2010
Subjects:	5-Lipoxygenase-Activating Proteins Adolescent Adult Aged Area Under Curve Biological and medical sciences Carrier Proteins - antagonists & inhibitors Dose-Response Relationship, Drug Double-Blind Method Female Humans Indoles - adverse effects Indoles - pharmacokinetics Indoles - pharmacology Leukotriene B4 - biosynthesis Leukotriene E4 - urine Male Medical sciences Membrane Proteins - antagonists & inhibitors Middle Aged Pharmacology. Drug treatments Propionates - adverse effects Propionates - pharmacokinetics Propionates - pharmacology Young Adult Human Pharmacodynamics 5-Lipoxygenase activating protein Inhibitor Flap (surgery) Pharmacokinetics Biological activity
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Summary:	The 5‐lipoxygenase‐activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability 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 FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose‐dependent inhibition of blood LTB4 production and dose‐related inhibition of urinary LTE4. After a single oral dose (50–1,000 mg) of AM103, the maximum concentration (Cmax) and area under the curve (AUC) in plasma increased in a dose‐dependent manner. After multiple‐dose administration (50–1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single‐ and multiple‐dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted. Clinical Pharmacology & Therapeutics (2010) 87 4, 437–444. doi:10.1038/clpt.2009.301
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-News-1 ObjectType-Feature-3 content type line 23
ISSN:	0009-9236 1532-6535
DOI:	10.1038/clpt.2009.301