Details

Autor(en) / Beteiligte

• Abdelrahman, Aliaa
• Yerande, Swapnil G
• Namasivayam, Vigneshwaran
• Klapschinski, Tim A
• Alnouri, Mohamad Wessam
• El-Tayeb, Ali
• Müller, Christa E

Titel

Substituted 4-phenylthiazoles: Development of potent and selective A 1 , A 3 and dual A 1 /A 3 adenosine receptor antagonists

Ist Teil von

• European journal of medicinal chemistry, 2020-01, Vol.186, p.111879

Ort / Verlag

France

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A , A , A and A adenosine receptors (ARs). A and A ARs are G -coupled, while A and A ARs inhibit cAMP production via G proteins. Antagonists for A and A ARs may be useful for the treatment of (neuro)inflammatory diseases including acute kidney injury and kidney failure, pulmonary diseases, and Alzheimer's disease. In the present study, we optimized the versatile 2-amino-4-phenylthiazole scaffold by introducing substituents at N2 and C5 to obtain A and A AR antagonists including dual-target compounds. Selective A antagonists with (sub)nanomolar potency were produced, e.g. 11 and 13. These compounds showed species differences being significantly more potent at the rat as compared to the human A AR, and were characterized as inverse agonists. Several potent and selective A AR antagonists, e.g. 7, 8, 17 and 22 (K values of 5-9 nM at the human A AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A /A antagonists (10, 18) were developed showing K values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A AR and a homology model of the A AR were performed to rationalize the observed structure-activity relationships.