| Abstrakt: |
Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a−aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a−aj. Binding studies using membranes from cells stably expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype selectivity. The EC50 of the AE activities of compounds 3m−o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal activity at the A3AR. |
