Details

Autor(en) / Beteiligte

• Härter, Michael
• Kalthof, Bernd
• Delbeck, Martina
• Lustig, Klemens
• Gerisch, Michael
• Schulz, Simone
• Kast, Raimund
• Meibom, Daniel
• Lindner, Niels

Titel

Novel non-xanthine antagonist of the A 2B adenosine receptor: From HTS hit to lead structure

Ist Teil von

• European journal of medicinal chemistry, 2018-11, Vol.163, p.763

Ort / Verlag

France

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• The A adenosine receptor is a G protein-coupled receptor that belongs to the four member family of adenosine receptors: A , A , A , A . While adenosine-mediated A receptor signaling attenuates acute inflammation, facilitates tissue adaptation to hypoxia, and induces increased ischemia tolerance under conditions of an acute insult, persistently elevated adenosine levels and A receptor signaling are characteristics of a number of chronic disease states. In this report we describe the discovery of certain thienouracils (thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones) as antagonists of the A adenosine receptor by high-throughput screening from our corporate substance collection. The structure optimization of the initial screening hits led to BAY-545, an A receptor antagonist that was suitable for in vivo testing. The structure optimization work, SAR that was derived from there, as well as the properties of BAY-545 are also described. In vivo efficacy of BAY-545 was demonstrated in two models of lung fibrosis and data is presented.