Referenced in: none

Automatically associated channels: Kir2.3

Title: Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide.

Authors: Marina Maria Carrozzo, Umberto Maria Battisti, Giuseppe Cannazza, Giulia Puia, Federica Ravazzini, Aurelia Falchicchio, Serena Perrone, Cinzia Citti, Krzysztof Jozwiak, Daniela Braghiroli, Carlo Parenti, Luigino Troisi

Journal, date & volume: Bioorg. Med. Chem., 2014 Sep 1 , 22, 4667-76

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25126714

Abstract
Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound.