Synthesis and SAR studies of analogues of 4-(3, 3-dimethyl-butyrylamino)-3, 5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as adenosine A2A receptor ligands with improved aqueous solubility. Issue 6 (15th March 2015)

• Record Type: Journal Article
• Authors: Mikkelsen, Gitte Kobberøe; Langgård, Morten; Schrøder, Tenna Juul; Kreilgaard, Mads; Jørgensen, Erling B.; Brandt, Guillaume; Griffon, Yann; Boffey, Ray; Bang-Andersen, Benny
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 6(2015)
• Page Start: 1212
• Page End: 1216
• Publication Date: 2015-03-15
• Subjects: HATU 2-(1H-7-azabenzotriazol-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate -- EDC N-ethyl-N′-dimethylaminopropyl-carbodiimide hydrochloride -- HOBt 1-hydroxy-benzotriazole -- DMAP 4-dimethylaminopyridine -- DMF dimethylformamide -- DMSO dimethyl sulfoxide -- 1, 2-DCE 1, 2-dichloroethane -- AcOH acetic acid; hA2A -- Solubility; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.01.062
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure–activity studies starting from 4-(3, 3-dimethylbutyrylamino)-3, 5-difluoro- N -thiazol-2-yl-benzamide (Lu AA41063, 4 ) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.