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

Autor(es):Mostrar menos -

Kalaba, Predrag ^[1] ; Ilic, Marija ^[1] ; Aher, Nilima Y. ^[1] ; Dragacevic, Vladimir ^[1] ; Wieder, Marcus ^[1] ; Zehl, Martin ^[2] ; Wackerlig, Judith ^[1] ; Beyl, Stanislav ^[3] ; Sartori, Simone B. ^[4] ; Ebner, Karl ^[4] ; Roller, Alexander ^[5] ; Lukic, Natalie ^[5] ; Beryozkina, Tetyana ^[6] ; Perez Gonzalez, Eduardo Rene ^[7] ; Neill, Philip ^[1] ; Khan, Jawad Akbar ^[8] ; Bakulev, Vasiliy ^[6] ; Leban, Johann Jakob ^[1] ; Hering, Steffen ^[3] ; Pifl, Christian ^[9] ; Singewald, Nicolas ^[4] ; Lubec, Jana ^[10] ; Urban, Ernst ^[1] ; Sitte, Harald H. ^[8] ; Langer, Thierry ^[1] ; Lubec, Gert ^[10]

Afiliação do(s) autor(es)

^[1] Univ Vienna, Fac Life Sci, Dept Pharmaceut Chem, Althanstr 14, A-1090 Vienna - Austria

^[2] Univ Vienna, Fac Chem, Dept Analyt Chem, Wahringer Str 38, A-1090 Vienna - Austria

^[3] Univ Vienna, Fac Life Sci, Dept Pharmacol & Toxicol, Althanstr 14, A-1090 Vienna - Austria

^[4] Leopold Franzens Univ Innsbruck, CMBI, Inst Pharm, Dept Pharmacol & Toxicol, A-6020 Innsbruck - Austria

^[5] Univ Vienna, Fac Chem, Xray Struct Anal Ctr, Wahringer Str 38, A-1090 Vienna - Austria

^[6] Ural Fed Univ, 19 Mira St, Ekaterinburg 620002 - Russia

^[7] Univ Sao Paulo State, Fac Sci & Technol, Dept Chem & Biochem, Lab Fine Organ Chem, Roberto Simonsen 305, BR-19060900 Presidente Prudente, SP - Brazil

^[8] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, A-1090 Vienna - Austria

^[9] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna - Austria

^[10] Paracelsus Med Univ, Neurosci Lab, A-5020 Salzburg - Austria

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 63, n. 1, p. 391-417, JAN 9 2020.
• Citações Web of Science: 4

Resumo

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. (AU)

• Processo FAPESP: 16/10149-0 - Síntese e caracterização química e biológica de análogos de 2-fenilquinazolinas-4-substituídas como novos inibidores atípicos do transporte e recaptação da dopamina (DAT)
• Beneficiário: Eduardo Rene Perez Gonzalez
• Modalidade de apoio: Bolsas no Exterior - Pesquisa