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.

Autor: Mikkelsen GK; Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. Electronic address: gmi@lundbeck.com., Langgård M; Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark., Schrøder TJ; Department of Molecular Pharmacology, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark., Kreilgaard M; Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark., Jørgensen EB; Biologics & Pharmaceutical Science Department, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark., Brandt G; Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK., Griffon Y; Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK., Boffey R; Argenta Discovery Ltd, 8-9 The Spire Green Centre, Harlow CM19 5TR, UK., Bang-Andersen B; Department of Discovery Chemistry & DMPK, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Mar 15; Vol. 25 (6), pp. 1212-6. Date of Electronic Publication: 2015 Feb 07.
DOI: 10.1016/j.bmcl.2015.01.062
Abstrakt: 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.
(Copyright © 2015 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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