Development of Polar Adenosine A(2A) Receptor Agonists for Inflammatory Bowel Disease: Synergism with A(2B) Antagonists

作者：El Tayeb Ali; Michael Sebastian; Abdelrahman Aliaa; Behrenswerth Andrea; Gollos Sabrina; Nieber Karen; Mueller Christa E

来源：ACS Medicinal Chemistry Letters, 2011, 2(12): 890-895.

DOI：10.1021/ml200189u

• A(2A) receptor agonist
• inflammatory bowel disease
• anti-inflammatory drug
• nonabsorbable A(2A) receptor agonist
• A(2B) receptor antagonist

Adenosine A(2A) receptor agonists for the local treatment of inflammatory bowel disease (IBS) were designed and synthesized. Polar groups were introduced to prevent peroral absorption and subsequent systemic, e.g., hypotensive, side effects. 4-(2-{6-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-2-ylthio}ethyl)-benzenesulfonic acid (7, PSB-0777) was selected for further evaluation in rat ileum/jejunum preparations in ex vivo experiments. Compound 7 significantly improved impaired acetylcholine-induced contractions induced by 2,4,6-trinitrobenzenesulfonic acid and showed synergism with an A(2B)-selective antagonist. Thus, nonabsorbable, locally active A(2A) agonists, as a monotherapy or in combination with an A(2B) antagonist, may be an efficient novel treatment for IBS, preventing the severe systemic side effects of known A(2A) agonists.

• 出版日期2011-12