An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives.

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously generates the C2 and C5 substituents in a stereoselective manner.

Integrating intramolecular hydrogen bonding (IMHB) considerations in drug discovery using ΔlogP as a tool.

This study demonstrates that ΔlogP(oct-tol) (difference between logP(octanol) and logP(toluene)) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates. We identified experimental protocols for acquiring reliable ΔlogP(oct-tol) values on a set of compounds representing IMHB motifs most prevalent in medicinal chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings. Furthermore, computational ΔlogP(oct-tol) values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB. The proposed interpretation method based on ΔlogP(oct-tol) data allowed categorization of the compounds into 2 groups: with high propensity to form IMHB and poor propensity or poor relevance of IMHB. The relative (1)H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.

Cardiac rate normalization in chronic atrial fibrillation: comparison of long-term efficacy of treatment with amiodarone versus AV node ablation and permanent His-bundle pacing.

Chronic atrial fibrillation (AF) is a common arrhythmia with significant morbidity and mortality. AF has been the subject of considerable attention and intensive clinical research in recent years. Current opinion on the management of AF favors the restoration and maintenance of normal ventricular rhythm. This has several potential benefits, including the alleviation of arrhythmia-associated symptoms and hemodynamic improvements. Maintenance of frequents normalization of ventricular rhythm (NVR) can be achieved with antiarrhythmic drug therapy or with AV node radiofrequency ablation (RFA) and permanent ventricular pacing. Recent interest has focused on the use of class III antiarrhythmic agents, such as amiodarone hydrochloride. This investigation compared amiodarone to AV node RFA and permanent pacing of the His-bundle area in maintaining NVR in patients with resistant chronic AF. After 12 months of treatment with amiodarone (200 to 400 mg/d) 30 % of patients remained in NVR, 30 % were in transitional phase of improvement, and 40 % showed negative effect. Only a few patients in this group developed ocular or hepatic side effects. On one year follow-up was achieved in 100 % of cases without any clinically significant side effects being seen. In conclusion, analysis of the results of this study suggests that low-dose amiodarone is well tolerated in the management of chronic AF in a selected patient population. The more aggressive interventional radiofrequency ablation technique is significantly more effective and more reliable in the long-term clinical treatment of drug-resistant AF.