Roflumilast analogs with improved metabolic stability, plasma protein binding, and pharmacokinetic profile

New LC methods were applied to evaluate the metabolic stability, plasma protein binding affinity and in vivo pharmacokinetic profiles of roflumilast analogs. All the tested compounds showed comparable pharmacokinetic profile to roflumilast. III can be considered as a good drug candidate for treating COPD. AbstractWith the aim of studying theirin vitro andin vivo pharmacokinetics, new chromatographic methods were developed for the determination of three new roflumilast synthetic analogs (I −III) as PDE ‐4B inhibitors in rat liver S9 fraction, phosphate buffered saline, pH 7.4, and human and rat plasma. The developed high performance liquid chromatography−ultra violet (HPLC−UV) methods were performed on a Zorbax Eclipse C8 column and UV detection was carried out at 215 nm. The three compoun ds were tested for their metabolic stability and were found to be metabolically more stable than roflumilast especially the 2‐mercaptobenzothiazol‐6‐yl analog (III) which displayed anin vitro half ‐life time (247.55 minutes) higher than that of roflumilast (12.29 minutes) and a lowin vitro clearance of 5.67  mL/min./kg. Possible phase I metabolites were investigated using ultra‐performance liquid chromatography−tandem mass spectrometry (UPLC–MS/MS) showing hydroxylation of the unsubstituted benzothiazol‐2‐yl (I) and benzothiazole ‐6‐yl (II) analogs and a cleaved benzothiazole metabolite of the 2 ‐mercaptobenzothiazol‐6‐yl analog (III). Plasma protein ...
Source: Drug Testing and Analysis - Category: Drugs & Pharmacology Authors: Tags: RESEARCH ARTICLE Source Type: research