Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor.

A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.

Pseudosaccharin amines as potent and selective KV1.5 blockers.

Phenethyl aminoheterocycles like compound 1 were known to be potent I(Kur) blockers although they lacked potency in vivo. Modification of the heterocycle led to the design and synthesis of pseudosaccharin amines. Compounds such as 14, 17d and 21c were found to be potent K(V)1.5 blockers and selective over other cardiac ion channels. These compounds had potent pharmacodynamic activity, however, they also showed off-target activities such as hemodynamic effects.

Triazolo and imidazo dihydropyrazolopyrimidine potassium channel antagonists.

Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective Kv1.5 inhibitor with an acceptable PK and liability profile.

Discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone as a potent and selective I(Kur) inhibitor.

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.

Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective KV1.5 blockers.

Design and synthesis of pyrazolodihydropyrimidines as KV1.5 blockers led to the discovery of 7d as a potent and selective antagonist. This compound showed atrial selective prolongation of effective refractory period in rabbits and was selected for clinical development.

Dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)).

A series of dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described.

Pyrano-[2,3b]-pyridines as potassium channel antagonists.

The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the I(Kur) channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC(50) of 378 nM.

Estimation of hERG inhibition of drug candidates using multivariate property and pharmacophore SAR.

We describe the development of a computational model for the prediction of the inhibition of K(+) flow through the hERG ion channel. Using a collection of 1075 discovery compounds with hERG inhibition measured in our standard patch-clamp electrophysiology assay, molecular features important for drug-induced inhibition were identified using a combination of statistical inference algorithms and manual hypothesis generation and testing. While many of the features used in the model reflect those referenced in the literature, several aspects of the model provide new insight into the role of physicochemical properties, electrostatics, and novel pharmacophores in hERG inhibition. Coefficients for these 10 features were then determined by least median squares regression, resulting in a model with an R(2) approximately 0.66 and RMS error (RMSe) of 0.47 log units for an external test set. Significant additional validation performed using a large collection of subsequent discovery data has been very encouraging with an R(2)=0.54 and an RMSe of 0.63 log units. The performance of the model across several different chemotypes is demonstrated and discussed.

Benzopyran sulfonamides as KV1.5 potassium channel blockers.

K(V)1.5 blockers have the potential to be atrium-selective agents for treatment of atrial fibrillation. The benzopyrans provide a template for the synthesis of potent and selective K(V)1.5 blockers.

Tetrahydronaphthalene-derived amino alcohols and amino ketones as potent and selective inhibitors of the delayed rectifier potassium current IKs.

Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.