ABSTRACT
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.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , Anti-Asthmatic Agents/chemical synthesis , Indoles/chemical synthesis , Pentanoic Acids/chemical synthesis , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacokinetics , 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , Administration, Oral , Animals , Anti-Asthmatic Agents/pharmacokinetics , Anti-Asthmatic Agents/pharmacology , Bronchoalveolar Lavage , Cytochrome P-450 Enzyme Inhibitors , Dogs , Female , Humans , In Vitro Techniques , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Pentanoic Acids/pharmacokinetics , Pentanoic Acids/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Carrier Proteins/antagonists & inhibitors , Indoles/pharmacokinetics , Leukotriene B4/antagonists & inhibitors , Membrane Proteins/antagonists & inhibitors , Propionates/pharmacokinetics , 5-Lipoxygenase-Activating Proteins , Animals , Asthma/drug therapy , Dogs , Drug-Related Side Effects and Adverse Reactions , Heterocyclic Compounds/chemistry , Humans , Inhibitory Concentration 50 , Leukotriene B4/biosynthesis , Mice , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
A water soluble choline prodrug (17) of a COX-2 selective inhibitor (16) suitable for intravenous dosing in models of cerebral ischemia has been developed. Constant infusion studies using 17 demonstrate that extrapolated brain levels of 16 may be maintained for over 24h in rats.
