2. Academic Validation
  3. Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters

  • J Med Chem. 2020 Jan 9;63(1):391-417. doi: 10.1021/acs.jmedchem.9b01938.
Predrag Kalaba 1,  Marija Ilić 1,  Nilima Y Aher 1,  Vladimir Dragačević 1,  Marcus Wieder 1,  Martin Zehl 2,  Judith Wackerlig 1,  Stanislav Beyl 3,  Simone B Sartori 4,  Karl Ebner 4,  Alexander Roller 5,  Natalie Lukic 5,  Tetyana Beryozkina 6,  Eduardo Rene Perez Gonzalez 7,  Philip Neill 1,  Jawad Akbar Khan 8,  Vasiliy Bakulev 6,  Johann Jakob Leban 1,  Steffen Hering 3,  Christian Pifl 9,  Nicolas Singewald 4,  Jana Lubec 10,  Ernst Urban 1,  Harald H Sitte 8,  Thierry Langer 1,  Gert Lubec 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Life Sciences , University of Vienna , Althanstraße 14 , 1090 Vienna , Austria.
  • 2 Department of Analytical Chemistry, Faculty of Chemistry , University of Vienna , Währinger Straße 38 , 1090 Vienna , Austria.
  • 3 Department of Pharmacology and Toxicology, Faculty of Life Sciences , University of Vienna , Althanstraße 14 , 1090 Vienna , Austria.
  • 4 Center for Molecular Biosciences Innsbruck (CMBI), Department of Pharmacology and Toxicology, Institute of Pharmacy , Leopold Franzens University Innsbruck , 6020 Innsbruck , Austria.
  • 5 X-ray Structure Analysis Centre, Faculty of Chemistry , University of Vienna , Währinger Straße 38 , 1090 Vienna , Austria.
  • 6 Ural Federal University Named after the First President of Russia B. N. Yeltsin , 19 Mira st. , Yekaterinburg 620002 , Russia.
  • 7 Laboratory of Fine Organic Chemistry, Department of Chemistry and Biochemistry, Faculty of Science and Technology , University of Sao Paulo State , Roberto Simonsen 305 , CEP 19060-900 , Presidente Prudente , SP , Brazil.
  • 8 Institute of Pharmacology, Centre of Physiology and Pharmacology , Medical University of Vienna , 1090 Vienna , Austria.
  • 9 Centre for Brain Research , Medical University of Vienna , 1090 Vienna , Austria.
  • 10 Neuroscience Laboratory , Paracelsus Medical University , A-5020 Salzburg , Austria.
PMID: 31841637 DOI: 10.1021/acs.jmedchem.9b01938
Abstract

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the Dopamine Transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the S-configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by in silico, in vitro, and in vivo studies that have demonstrated both safety and efficacy profile of this compound class.

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