title: 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.
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. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 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.
authors.affiliation: Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. Electronic address: gmi@lundbeck.com.
authors.forename: Gitte Kobberøe
authors.initials: GK
authors.lastname: Mikkelsen
authors.affiliation: Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Langgård
authors.affiliation: Department of Molecular Pharmacology, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Tenna Juul
authors.initials: TJ
authors.lastname: Schrøder
authors.affiliation: Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Biologics & Pharmaceutical Science Department, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Erling B
authors.initials: EB
authors.lastname: Jørgensen
authors.affiliation: Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Brandt
authors.affiliation: Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK.
authors.forename: Yann
authors.initials: Y
authors.lastname: Griffon
authors.affiliation: Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK.
authors.forename: Ray
authors.initials: R
authors.lastname: Boffey
authors.affiliation: Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D014867:Water / Q000737:chemistry; D062366:para-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C000603766:4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-ylbenzamide; D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A; D013844:Thiazoles; D062366:para-Aminobenzoates; D014867:Water
keywords: Solubility; hA(2A)