ABSTRACT
Two new water-soluble cellulose derivatives were prepared by a two-step transformation with 1,3-propane sultone, followed by either maleic or succinic anhydride, thereby converting cellulose into a more easily processable form. It was found that the solubility was dependent on both the degree of substitution and the chemical properties of the substituents. The water-soluble cellulose has a molecular weight greater than 100 000 g mol-1 and both the morphology and molecular weight can be tuned by varying the reaction conditions. Furthermore, the flexible, two-step nature of the process allows for expansion of this methodology in order to prepare cellulose analogues for different applications.
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
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 µM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
