1. 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.
- Author
-
Carrozzo MM, Battisti UM, Cannazza G, Puia G, Ravazzini F, Falchicchio A, Perrone S, Citti C, Jozwiak K, Braghiroli D, Parenti C, and Troisi L
- Subjects
- Allosteric Regulation drug effects, Benzothiadiazines chemical synthesis, Benzothiadiazines chemistry, Crystallography, X-Ray, Cyclic S-Oxides chemical synthesis, Cyclic S-Oxides chemistry, Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Stereoisomerism, Structure-Activity Relationship, Benzothiadiazines pharmacology, Cyclic S-Oxides pharmacology, Drug Design, Receptors, AMPA metabolism
- 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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF