ABSTRACT
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
A 'global' model of hERG K(+) channel was built to satisfy three basic criteria for QSAR models in drug discovery: (1) assessment of the applicability domain, (2) assuring that model decisions can be interpreted by medicinal chemists and (3) assessment of model performance after the model was built. A combination of D-optimal onion design and hierarchical partial least squares modelling was applied to construct a global model of hERG blockade in order to maximize the applicability domain of the model and to enhance its interpretability. Additionally, easily interpretable hERG specific fragment-based descriptors were developed. Model performance was monitored, throughout a time period of 15 months, after model implementation. It was found that after this time duration a greater proportion of molecules were outside the model's applicability domain and that these compounds had a markedly higher average prediction error than those from molecules within the model's applicability domain. The model's predictive performance deteriorated within 4 months after building, illustrating the necessity of regular updating of global models within a drug discovery environment.