ABSTRACT
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
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Subject(s)
Kv1.5 Potassium Channel/antagonists & inhibitors , Lactams/chemistry , Potassium Channel Blockers/chemistry , Pyrrolidinones/chemistry , Sulfonamides/chemistry , Animals , Dogs , Half-Life , Humans , Kv1.5 Potassium Channel/metabolism , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacokinetics , Pyrrolidinones/chemical synthesis , Pyrrolidinones/pharmacokinetics , Rabbits , Rats , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
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
In the presence of iodotrimethylsilane (TMSI) and lithium iodide in tetrahydrofuran, the otherwise unreactive copper acetylides add to enones present as s-trans conformers to provide good yields of the silyl enol ethers of beta-acetylido carbonyl compounds. Typically good substrates are 2-cyclopentenone, 2-cyclohexenone, alpha,beta-unsaturated aldehydes, and beta-alkoxy-alpha-enones. Copper acetylide reagents prepared from CuI and an alkynyllithium give considerably higher yields than those prepared from CuBr or CuCN. Iodotrimethylsilane is by far the most efficient silane, although trimethylsilyl triflate is useful in some cases.
