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Substituted 4-phenylthiazoles: Development of potent and selective A1, A3 and dual A1/A3 adenosine receptor antagonists
Ist Teil von
European journal of medicinal chemistry, 2020-01, Vol.186, p.111879-111879, Article 111879
Ort / Verlag
Elsevier Masson SAS
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Elsevier ScienceDirect Journals Complete
Beschreibungen/Notizen
Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A1, A2A, A2B and A3 adenosine receptors (ARs). A2A and A2B ARs are Gs-coupled, while A1 and A3 ARs inhibit cAMP production via Gi proteins. Antagonists for A1 and A3 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 A1 and A3 AR antagonists including dual-target compounds. Selective A1 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 A1 AR, and were characterized as inverse agonists. Several potent and selective A3 AR antagonists, e.g. 7, 8, 17 and 22 (Ki values of 5–9 nM at the human A3 AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A1/A3 antagonists (10, 18) were developed showing Ki values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A1 AR and a homology model of the A3 AR were performed to rationalize the observed structure-activity relationships.
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•2-Amino-4-phenylthiazole derivatives were designed as A1-, A3-, or dual A1/A3-adenosine receptor (AR) antagonists.•Selective A1 AR antagonists with inverse agonistic activity showing (sub)nanomolar potency were obtained.•Selective A3 AR antagonists showing nanomolar potency were identified.•Species differences (human/rat) were observed for both AR subtypes.•Potent dual antagonists for A1 and A3 AR were developed as potential therapeutics for treating kidney failure, pulmonary diseases, and Alzheimer’s disease.