ABSTRACT
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
Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) 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 LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), 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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carrier Proteins/antagonists & inhibitors , Indoles/pharmacology , Inflammation/drug therapy , Membrane Proteins/antagonists & inhibitors , Propionates/pharmacology , 5-Lipoxygenase-Activating Proteins , Acute Disease , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Asthma/drug therapy , Asthma/enzymology , Asthma/metabolism , Chronic Disease , Disease Models, Animal , Dose-Response Relationship, Drug , Extravasation of Diagnostic and Therapeutic Materials/drug therapy , Extravasation of Diagnostic and Therapeutic Materials/enzymology , Extravasation of Diagnostic and Therapeutic Materials/metabolism , Female , Humans , Indoles/therapeutic use , Inflammation/enzymology , Inflammation/metabolism , Leukotriene B4/biosynthesis , Leukotriene B4/blood , Male , Mice , Mice, Inbred BALB C , Pneumonia/drug therapy , Pneumonia/enzymology , Pneumonia/metabolism , Propionates/therapeutic use , Rats , Rats, Sprague-Dawley , ZymosanABSTRACT
The SAR of the lead compound 3, a novel ligand for the alpha(2)delta subunit of voltage-gated calcium channels, was rapidly explored. Utilizing a parallel solution-phase Sn2Ar coupling approach, a focused library was obtained. The library was evaluated in vitro and afforded a series of analogues with improved potencies. The SAR trends of the library are also described.
Subject(s)
Calcium Channels/metabolism , Combinatorial Chemistry Techniques/methods , Ion Channel Gating , Protein Subunits/metabolism , Calcium Channels/chemistry , Calcium Channels/drug effects , Humans , Ligands , Protein Subunits/chemistry , Solutions/chemistry , Structure-Activity RelationshipABSTRACT
A novel class of 2H-pyrrolo[3,4-c]pyridazine ligands of the alpha (2) delta subunit of voltage-gated calcium channels is described. Compound 4a with high affinity toward alpha (2) delta was identified through structure-activity relationship studies of the lead compound. Tritiated ligand [(3)H]-4b was synthesized to demonstrate that this ligand binds to the same site as Gabapentin toward alpha (2) delta subunit of voltage-gated calcium channels.
Subject(s)
Calcium Channels/drug effects , Ion Channel Gating , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Drug Evaluation, Preclinical , Ligands , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
A novel class of 6-aryl-6H-pyrrolo[3,4-d]pyridazine ligands for the alpha2delta subunit of voltage-gated calcium channels has been described. Substitutions in the aryl ring of the molecule were generally not tolerated, and resulted in diminished binding to the alpha2delta subunit. Modifications to the pyridazine ring revealed numerous permissive substitutions, and detailed SAR studies were carried out in this portion of the molecule. Replacement of the pyridazine ring methyl group with an aminomethyl functionality provided greatly improved potency over the initial lead. The initial lead compound displayed good rat pharmacokinetic properties, and was shown to be efficacious in the Chung model for neuropathic pain in rats.
