2. Academic Validation
  3. Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

  • Molecules. 2020 Feb 19;25(4):935. doi: 10.3390/molecules25040935.
Valeria Cavalloro 1 2,  Katia Russo 1,  Francesca Vasile 3,  Luca Pignataro 3,  Archimede Torretta 4,  Stefano Donini 4,  Marta S Semrau 5,  Paola Storici 5,  Daniela Rossi 1,  Federica Rapetti 6,  Chiara Brullo 6,  Emilio Parisini 4 7,  Olga Bruno 6,  Simona Collina 1
Affiliations

Affiliations

  • 1 Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.
  • 2 Department of Earth and Environmental Sciences, University of Pavia, 27100 Pavia, Italy.
  • 3 Università degli Studi di Milano, Dipartimento di Chimica, via C. Golgi 19, 20133 Milano, Italy.
  • 4 Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy.
  • 5 Elettra-Sincrotrone Trieste S.C.p.A., SS 14-km 163.5 in AREA Science Park, 34149 Trieste, Italy.
  • 6 Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy.
  • 7 Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
PMID: 32093112 DOI: 10.3390/molecules25040935
Abstract

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D Enzyme by interacting with both the catalytic pocket and the regulatory domains.

Keywords

HPLC chiral resolution; NMR absolute configuration assignment; PDE4 inhibition.

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