6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines:  A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency

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.