ABSTRACT
5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC50 hWBfree of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B4 (LTB4) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB4 levels in humans. Compound 4i is progressed to preclinical in vivo safety studies.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/pharmacology , Cyclohexanes/pharmacology , Pyrazoles/pharmacology , 5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , 5-Lipoxygenase-Activating Protein Inhibitors/toxicity , Animals , Caco-2 Cells , Coronary Artery Disease/drug therapy , Cyclohexanes/chemical synthesis , Cyclohexanes/toxicity , Dogs , Female , Humans , Leukotriene B4/antagonists & inhibitors , Male , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Subject(s)
Isoindoles/pharmacology , Kv1.5 Potassium Channel/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Isoindoles/chemical synthesis , Isoindoles/chemistry , Mice , Models, Animal , Molecular Structure , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/chemistry , Structure-Activity RelationshipABSTRACT
Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110ß isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110α, (S)-21 did not induce any insulin resistance in rats.
Subject(s)
1-Phosphatidylinositol 4-Kinase/antagonists & inhibitors , Blood Platelets/drug effects , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Drug Discovery , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacology , Morpholines/chemical synthesis , Morpholines/pharmacology , Protein Isoforms/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Animals , Bleeding Time , Dogs , Fibrinolytic Agents/chemistry , Inhibitory Concentration 50 , Insulin Resistance , Molecular Structure , Morpholines/chemistry , Pyrimidinones/chemistry , RatsABSTRACT
The discovery of 4-morpholino-pyrimidin-6-one and 4-morpholino-pyrimidin-2-one-containing inhibitors of Phosphoinositide 3-kinases (PI3K) p110ß isoform is reported. Structure-based optimisation of the original fragment hit resulted in lead compounds with improvements in ligand efficiency, lipophilicity efficiency, p110ß potency and selectivity over p110α.
Subject(s)
Drug Discovery , Enzyme Inhibitors/chemistry , Phosphoinositide-3 Kinase Inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Morpholines/chemical synthesis , Morpholines/chemistry , Morpholines/pharmacology , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Protein Binding/drug effects , Protein Isoforms/antagonists & inhibitors , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , SolubilityABSTRACT
Two libraries of alpha-substituted alkynes has been prepared on solid phase using a sequential Sonogashira/Nicholas reaction approach. The scope of nucleophiles in the Nicholas reaction on solid phase has been investigated, including carbon, oxygen, nitrogen, sulfur, fluoride, and hydride nucleophiles. The conditions for the reaction sequence have been optimized in terms of Lewis acid, catalyst for the Sonogashira step, temperature, reaction time, and decomplexation method, enabling the five-step sequence to be performed in 1 day.
Subject(s)
Alkynes/chemical synthesis , Chemistry, Pharmaceutical , Combinatorial Chemistry Techniques , Carbon/chemistry , Catalysis , Fluorides/chemistry , Hydrocarbons, Halogenated/chemistry , Models, Chemical , Nitrogen/chemistry , Oxygen/chemistry , Palladium/chemistry , Reaction Time , Resins, Synthetic/chemistry , Sulfur/chemistry , TemperatureABSTRACT
The first example of a Nicholas reaction on solid phase is reported, involving the reaction of cobalt complexes of polymer-bound alkynols with different nucleophiles in the presence of a Lewis acid, to form carbon-oxygen or carbon-carbon bonds.
